Combination of Aurora Kinase Inhibitors and Anti-CD20 Antibodies

ABSTRACT

The present invention relates to methods for the treatment of hematological malignancies. In particular, the invention provides methods for treatment of hematological malignancies by administering Aurora kinase inhibitors in combination with anti-CD20 antibodies.

RELATED APPLICATIONS

The present application claims the benefit of U.S. ProvisionalApplication Ser. No. 61/203,509, filed Dec. 22, 2008 (pending), thecontents of which are incorporated herein by reference.

FIELD OF THE INVENTION

This invention relates to methods for the treatment of hematologicalmalignancies. In particular, the invention provides methods fortreatment of hematological malignancies by administering Aurora kinaseinhibitors in combination with anti-CD20 antibodies.

BACKGROUND OF THE INVENTION

According to the American Cancer Society, an estimated 1.4 millionAmericans were newly-diagnosed with cancer in 2004 and about 560,000victims died from the disease. While medical advance have improvedcancer survival rates, there is a continuing need for new and moreeffective treatment.

Cancer is characterized by uncontrolled cell reproduction. Mitosis is astage in the cell cycle during which a series of complex events ensurethe fidelity of chromosome separation into two daughter cells. Severalcurrent cancer therapies, including the taxanes and vinca alkaloids, actto inhibit the mitotic machinery. Mitotic progression is largelyregulated by proteolysis and by phosphorylation events that are mediatedby mitotic kinases. Aurora kinase family members (e.g., Aurora A, AuroraB, Aurora C) regulate mitotic progression through modulation ofcentrosome separation, spindle dynamics, spindle assembly checkpoint,chromosome alignment/segregation, and cytokinesis (Dutertre et al.,Oncogene, 21: 6175 (2002); Berdnik et al., Curr. Biol., 12: 640 (2002)).Overexpression and/or amplification of Aurora kinases have been linkedto oncogenesis in several tumor types including those of colon andbreast (Warner et al., Mol. Cancer. Ther., 2: 589 (2003); Bischoff etal., EMBO, 17: 3062 (1998); Sen et al., Cancer Res., 94: 1320 (2002)).Moreover, Aurora kinase inhibition in tumor cells results in mitoticarrest and apoptosis, suggesting that these kinases are importanttargets for cancer therapy (Manfredi et al., PNAS., 104: 4106 (2007);Ditchfield, J. Cell Biol., 161: 267 (2003); Harrington et al., NatureMed., 1 (2004)). Given the central role of mitosis in the progression ofvirtually all malignancies, inhibitors of the Aurora kinases areexpected to have application across a broad range of human tumors.

CD20 (also known as Bp35) is a B-lymphocyte-restricted differentiationantigen that is expressed during early pre-B-cell development andremains until plasma cell differentiation. CD20 is a useful target forB-cell lymphomas as this antigen is expressed at very high densities onthe surface of malignant B-cells, i.e., B-cells wherein unabatedproliferation can lead to B-cell lymphomas. The Food and DrugAdministration has approved the therapeutic use of an anti-CD20antibody, rituximab (RITUXAN®), for use in relapsed and previouslytreated low-grade non-Hodgkin's lymphoma (NHL). Rituximab acts bybinding to the CD20 antigen on B cells which results in the lysis of theB cell by a mechanism thought to involve complement-dependentcytotoxicity (CDC) and antibody-dependent cell mediated cytotoxicity(ADCC).

However, while anti-CD20 antibodies and, in particular, rituximab, havebeen reported to be effective for treatment of B-cell lymphomas, such asnon-Hodgkin's lymphoma, the treated patients are often subject todisease relapse. Therefore, it would be beneficial if more effectivetreatment regimens could be developed. Combined treatment regimens couldbe helpful for patients suffering from B cell related tumors or otherhematological malignancies, and might potentially even decrease the rateof relapse or overcome the resistance to a particular anticancer agentsometime seen in these patients. Additionally, combinations ofanticancer agents may have additive, or even synergistic, therapeuticeffects.

There is thus a need for new cancer treatment regimens, includingcombination therapies.

DESCRIPTION OF THE INVENTION

The present invention provides new combination therapies for thetreatment of hematological malignancies. In particular, the presentinvention provides a method to treat a patient suffering from ahematological malignancy comprising administering to said patient atherapeutically effective amount of a Aurora kinase inhibitorsimultaneously with or consecutively with (e.g., before or after) ananti-CD20 antibody.

Terms used herein shall be accorded the following defined meanings,unless otherwise indicated.

As used herein, the term “Aurora kinase” refers to any one of a familyof related serine/threonine kinases involved in mitotic progression. Avariety of cellular proteins that play a role in cell division aresubstrates for phosphorylation by Aurora kinase enzymes, including,without limitation, histone H3, p53, CENP-A, myosin II regulatory lightchain, protein phosphatase-1, TPX-2, INCENP, survivin, topoisomerase IIalpha, vimentin, MBD-3, MgcRacGAP, desmin, Ajuba, XIEg5 (in Xenopus),Ndc10p (in budding yeast), and D-TACC (in Drosophila). Aurora kinaseenzymes also are themselves substrates for autophosphorylation, e.g., atThr288. Unless otherwise indicated by context, the term “Aurora kinase”is meant to refer to any Aurora kinase protein from any species,including, without limitation, Aurora A, Aurora B, and Aurora C,preferably Aurora A or B. Preferably, the Aurora kinase is a humanAurora kinase.

The term “Aurora kinase inhibitor” or “inhibitor of Aurora kinase” isused to signify a compound which is capable of interacting with anAurora kinase and inhibiting its enzymatic activity. Inhibiting Aurorakinase enzymatic activity means reducing the ability of an Aurora kinaseto phosphorylate a substrate peptide or protein. In various embodiments,such reduction of Aurora kinase activity is at least about 50%, at leastabout 75%, at least about 90%, at least about 95%, or at least about99%. In various embodiments, the concentration of Aurora kinaseinhibitor required to reduce an Aurora kinase enzymatic activity is lessthan about 1 μM, less than about 500 nM, less than about 100 nM, or lessthan about 50 nM.

In some embodiments, such inhibition is selective, i.e., the Aurorakinase inhibitor reduces the ability of an Aurora kinase tophosphorylate a substrate peptide or protein at a concentration that islower than the concentration of the inhibitor that is required toproduce another, unrelated biological effect, e.g., reduction of theenzymatic activity of a different kinase. In some embodiments, theAurora kinase inhibitor also reduces the enzymatic activity of anotherkinase, preferably one that is implicated in cancer.

The term “about” is used herein to mean approximately, in the region of,roughly, or around. When the term “about” is used in conjunction with anumerical range, it modifies that range by extending the boundariesabove and below the numerical values set forth. In general, the term“about” is used herein to modify a numerical value above and below thestated value by a variance of 10%.

As used herein, the term “comprises” means “includes, but is not limitedto.”

A “CD20” antigen is a 35 kDa, non-glycosylated phosphoprotein found onthe surface of greater than 90% of B cells from peripheral blood orlymphoid organs. CD20 is expressed during early pre-B cell developmentand remains until plasma cell differentiation. CD20 is present on bothnormal B cells as well as malignant B cells. Other names for CD20 in theliterature include “B-lymphocyte-restricted antigen” and “Bp35”.

The CD20 antigen is described in, e.g., Clark et al. PNAS (USA) 82:1766(1985).

The term “antibody” herein is used in the broadest sense andspecifically covers intact monoclonal antibodies, polyclonal antibodies,humanized antibodies, human antibodies, chimeric antibodies,multispecific antibodies (e.g., bispecific antibodies) formed from atleast two intact antibodies, and antibody fragments, so long as theyexhibit the desired biological activity. Antibodies may be produced byone of skill in the art using conventional methods.

The term “monoclonal antibody” as used herein refers to an antibodyobtained from a population of substantially homogeneous antibodies,i.e., the individual antibodies comprising the population are identicalexcept for possible naturally occurring mutations that may be present inminor amounts. Monoclonal antibodies are highly specific, being directedagainst a single antigenic site. Furthermore, in contrast toconventional (polyclonal) antibody preparations, which typically includedifferent antibodies directed against different determinants (epitopes),each monoclonal antibody is directed against a single determinant on theantigen. In addition to their specificity, the monoclonal antibodies areadvantageous in that they are synthesized by the hybridoma culture,uncontaminated by other immunoglobulins. The modifier “monoclonal”indicates the character of the antibody as being obtained from asubstantially homogeneous population of antibodies, and is not to beconstrued as requiring production of the antibody by any particularmethod. For example, the monoclonal antibodies to be used in accordancewith the present invention may be made by the hybridoma method firstdescribed by Kohler et al., Nature, 256:495 (1975), or may be made byrecombinant DNA methods (see, e.g., U.S. Pat. No. 4,816,567). The“monoclonal antibodies” may also be isolated from phage antibodylibraries using the techniques described in Clackson et al., Nature,352:624-628 (1991) and Marks et al, J. Mol. Biol., 222:581-597 (1991),for example. The monoclonal antibodies herein specifically include butare not limited to “chimeric” or “humanized” forms.

The term “aliphatic” or “aliphatic group”, as used herein, means asubstituted or unsubstituted straight-chain, branched or cyclic C₁₋₁₂hydrocarbon, which is completely saturated or which contains one or moreunits of unsaturation, but which is not aromatic. For example, suitablealiphatic groups include substituted or unsubstituted linear, branchedor cyclic alkyl, alkenyl, alkynyl groups and hybrids thereof, such as(cylcoalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

The terms “alkyl”, “alkenyl”, and “alkynyl”, used alone or as part of alarger moiety, refer to a straight and branched chain aliphatic grouphaving from 1 to 12 carbon atoms. For purposes of the present invention,the term “alkyl” will be used when the carbon atom attaching thealiphatic group to the rest of the molecule is a saturated carbon atom.However, an alkyl group may include unsaturation at other carbon atoms.Thus, alkyl groups include, without limitation, methyl, ethyl, propyl,allyl, propargyl, butyl, pentyl, and hexyl.

For purposes of the present invention, the term “alkenyl” will be usedwhen the carbon atom attaching the aliphatic group to the rest of themolecule forms part of a carbon-carbon double bond. Alkenyl groupsinclude, without limitation, vinyl, 1-propenyl, 1-butenyl, 1-pentenyl,and 1-hexenyl.

For purposes of the present invention, the term “alkynyl” will be usedwhen the carbon atom attaching the aliphatic group to the rest of themolecule forms part of a carbon-carbon triple bond. Alkynyl groupsinclude, without limitation, ethynyl, 1-propynyl, 1-butynyl, 1-pentynyl,and 1-hexynyl.

The term “cycloaliphatic”, used alone or as part of a larger moiety,refers to a saturated or partially unsaturated cyclic aliphatic ringsystem having from 3 to about 14 members, wherein the aliphatic ringsystem is optionally substituted. In some embodiments, thecycloaliphatic is a monocyclic hydrocarbon having 3-8 or 3-6 ring carbonatoms. Nonlimiting examples include cyclopropyl, cyclobutyl,cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl,cycloheptenyl, cyclooctyl, cyclooctenyl, and cyclooctadienyl. In someembodiments, the cycloaliphatic is a bridged or fused bicyclichydrocarbon having 6-12, 6-10, or 6-8 ring carbon atoms, wherein anyindividual ring in the bicyclic ring system has 3-8 members.

In some embodiments, two adjacent substituents on the cycloaliphaticring, taken together with the intervening ring atoms, form an optionallysubstituted fused 5- to 6-membered aromatic or 3- to 8-memberednon-aromatic ring having 0-3 ring heteroatoms selected from the groupconsisting of O, N, and S. Thus, the term “cycloaliphatic” includesaliphatic rings that are fused to one or more aryl, heteroaryl, orheterocyclyl rings. Nonlimiting examples include indanyl,5,6,7,8-tetrahydroquinoxalinyl, decahydronaphthyl, ortetrahydronaphthyl, where the radical or point of attachment is on thealiphatic ring. The term “cycloaliphatic” may be used interchangeablywith the terms “carbocycle”, “carbocyclyl”, “carbocyclo”, or“carbocyclic”.

The terms “aryl” and “ar-”, used alone or as part of a larger moiety,e.g., “aralkyl”, “aralkoxy”, or “aryloxyalkyl”, refer to a C6 to C14aromatic hydrocarbon, comprising one to three rings, each of which isoptionally substituted. Preferably, the aryl group is a C₆₋₁₀ arylgroup. Aryl groups include, without limitation, phenyl, naphthyl, andanthracenyl. In some embodiments, two adjacent substituents on the arylring, taken together with the intervening ring atoms, form an optionallysubstituted fused 5- to 6-membered aromatic or 4- to 8-memberednon-aromatic ring having 0-3 ring heteroatoms selected from the groupconsisting of O, N, and S. Thus, the term “aryl”, as used herein,includes groups in which an aromatic ring is fused to one or moreheteroaryl, cycloaliphatic, or heterocyclyl rings, where the radical orpoint of attachment is on the aromatic ring. Nonlimiting examples ofsuch fused ring systems include indolyl, isoindolyl, benzothienyl,benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl,quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl,quinoxalinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl,phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, fluorenyl,indanyl, phenanthridinyl, tetrahydronaphthyl, indolinyl, phenoxazinyl,benzodioxanyl, and benzodioxolyl. An aryl group may be mono-, bi-, tri-,or polycyclic, preferably mono-, bi-, or tricyclic, more preferablymono- or bicyclic. The term “aryl” may be used interchangeably with theterms “aryl group”, “aryl moiety”, and “aryl ring”.

An “aralkyl” or “arylalkyl” group comprises an aryl group covalentlyattached to an alkyl group, either of which independently is optionallysubstituted. Preferably, the aralkyl group is C₆₋₁₀ aryl(C₁₋₆)alkyl,C₆₋₁₀ aryl(C₁₋₄)alkyl, or C₆₋₁₀ aryl(C₁₋₃)alkyl, including, withoutlimitation, benzyl, phenethyl, and naphthylmethyl.

The terms “heteroaryl” and “heteroar-”, used alone or as part of alarger moiety, e.g., heteroaralkyl, or “heteroaralkoxy”, refer to groupshaving 5 to 14 ring atoms, preferably 5, 6, 9, or 10 ring atoms; having6, 10, or 14 π electrons shared in a cyclic array; and having, inaddition to carbon atoms, from one to four heteroatoms. The term“heteroatom” refers to nitrogen, oxygen, or sulfur, and includes anyoxidized form of nitrogen or sulfur, and any quaternized form of a basicnitrogen. Heteroaryl groups include, without limitation, thienyl,furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl,oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl,thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl,purinyl, naphthyridinyl, and pteridinyl. In some embodiments, twoadjacent substituents on the heteroaryl, taken together with theintervening ring atoms, form an optionally substituted fused 5- to6-membered aromatic or 4- to 8-membered non-aromatic ring having 0-3ring heteroatoms selected from the group consisting of O, N, and S.Thus, the terms “heteroaryl” and “heteroar-”, as used herein, alsoinclude groups in which a heteroaromatic ring is fused to one or morearyl, cycloaliphatic, or heterocyclyl rings, where the radical or pointof attachment is on the heteroaromatic ring. Nonlimiting examplesinclude indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl,indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl,cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl,carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl,tetrahydroquinolinyl, tetrahydroisoquinolinyl, andpyrido[2,3-b]-1,4-oxazin-3(4H)-one. A heteroaryl group may be mono-,bi-, tri-, or polycyclic, preferably mono-, bi-, or tricyclic, morepreferably mono- or bicyclic. The term “heteroaryl” may be usedinterchangeably with the terms “heteroaryl ring”, “heteroaryl group”, or“heteroaromatic”, any of which terms include rings that are optionallysubstituted. The term “heteroaralkyl” refers to an alkyl groupsubstituted by a heteroaryl, wherein the alkyl and heteroaryl portionsindependently are optionally substituted.

As used herein, the terms “heterocycle”, “heterocyclyl”, “heterocyclicradical”, and “heterocyclic ring” are used interchangeably and refer toa stable 3- to 7-membered monocyclic, or to a fused 7- to 10-membered orbridged 6- to 10-membered bicyclic heterocyclic moiety that is eithersaturated or partially unsaturated, and having, in addition to carbonatoms, one or more, preferably one to four, heteroatoms, as definedabove. When used in reference to a ring atom of a heterocycle, the term“nitrogen” includes a substituted nitrogen. As an example, in aheterocyclyl ring having 1-3 heteroatoms selected from oxygen, sulfur ornitrogen, the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (asin pyrrolidinyl) or ⁺NR (as in N-substituted pyrrolidinyl). Aheterocyclic ring can be attached to its pendant group at any heteroatomor carbon atom that results in a stable structure, and any of the ringatoms can be optionally substituted. Examples of such saturated orpartially unsaturated heterocyclic radicals include, without limitation,tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, pyrrolidonyl,piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl,diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl.

In some embodiments, two adjacent substituents on a heterocyclic ring,taken together with the intervening ring atoms, for an optionallysubstituted fused 5- to 6-membered aromatic or 3- to 8-memberednon-aromatic ring having 0-3 ring heteroatoms selected from the groupconsisting of O, N, and S. Thus, the terms “heterocycle”,“heterocyclyl”, “heterocyclyl ring”, “heterocyclic group”, “heterocyclicmoiety”, and “heterocyclic radical”, are used interchangeably herein,and include groups in which a heterocyclyl ring is fused to one or morearyl, heteroaryl, or cycloaliphatic rings, such as indolinyl,3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl, wherethe radical or point of attachment is on the heterocyclyl ring. Aheterocyclyl group may be mono-, bi-, tri-, or polycyclic, preferablymono-, bi-, or tricyclic, more preferably mono- or bicyclic. The term“heterocyclylalkyl” refers to an alkyl group substituted by aheterocyclyl, wherein the alkyl and heterocyclyl portions independentlyare optionally substituted.

As used herein, the term “partially unsaturated” refers to a ring moietythat includes at least one double or triple bond between ring atoms. Theterm “partially unsaturated” is intended to encompass rings havingmultiple sites of unsaturation, but is not intended to include aryl orheteroaryl moieties, as herein defined.

The terms “haloaliphatic”, “haloalkyl”, “haloalkenyl” and “haloalkoxy”refer to an aliphatic, alkyl, alkenyl or alkoxy group, as the case maybe, which is substituted with one or more halogen atoms. As used herein,the term “halogen” or “halo” means F, Cl, Br, or I. The term“fluoroaliphatic” refers to a haloaliphatic wherein the halogen isfluoro.

The term “alkylene” refers to a bivalent alkyl group. An “alkylenechain” is a polymethylene group, i.e., —(CH₂)_(n)—, wherein n is apositive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylenegroup in which one or more methylene hydrogen atoms is replaced with asubstituent. Suitable substituents include those described below for asubstituted aliphatic group. An alkylene chain also may be substitutedat one or more positions with an aliphatic group or a substitutedaliphatic group.

The term “substituted”, as used herein, means that a hydrogen radical ofthe designated moiety is replaced with the radical of a specifiedsubstituent, provided that the substitution results in a stable orchemically feasible compound. The phrase “one or more substituents”, asused herein, refers to a number of substituents that equals from one tothe maximum number of substituents possible based on the number ofavailable bonding sites, provided that the above conditions of stabilityand chemical feasibility are met. Unless otherwise indicated, anoptionally substituted group may have a substituent at eachsubstitutable position of the group, and the substituents may be eitherthe same or different.

An aryl (including the aryl moiety in aralkyl, aralkoxy, aryloxyalkyland the like) or heteroaryl (including the heteroaryl moiety inheteroaralkyl and heteroaralkoxy and the like) group may contain one ormore substituents. Examples of suitable substituents on the unsaturatedcarbon atom of an aryl or heteroaryl group include -halo, —NO₂, —CN,—R*, —C(R*)═C(R*)₂, —C≡C—R*, —OR*, —SR^(o), —S(O)R^(o), —SO₂R^(o),—SO₃R^(o), —SO₂N(R⁺)₂, —N(R⁺)₂, —NR⁺C(O)R*, —NR⁺C(O)N(R⁺)₂,—NR⁺CO₂R^(o), —O—CO₂R*, —OC(O)N(R⁺)₂, —O—C(O)R*, —CO₂R*, —C(O)—C(O)R*,—C(O)R*, —C(O)N(R⁺)₂, —C(O)N(R⁺)C(═NR⁺)—N(R⁺)₂,—N(R⁺)C(═NR⁺)—N(R⁺)—C(O)R*, —C(═NR⁺)—N(R⁺)₂, —C(═NR⁺)—OR*,—N(R⁺)—N(R⁺)₂, —N(R⁺)C(═NR⁺)—N(R⁺)₂, —NR⁺SO₂R^(o), —NR⁺SO₂N(R⁺)₂,—P(O)(R*)₂, —P(O)(OR*)₂, —O—P(O)—OR*, and —P(O)(NR⁺)—N(R⁺)₂; or twoadjacent substituents, taken together with their intervening atoms, forma 5-6 membered unsaturated or partially unsaturated ring having 0-3 ringatoms selected from the group consisting of N, O, and S.

An aryl (including the aryl moiety in aralkyl, aralkoxy, aryloxyalkyland the like) or heteroaryl (including the heteroaryl moiety inheteroaralkyl and heteroaralkoxy and the like) group may contain one ormore substituents. Examples of suitable substituents on the unsaturatedcarbon atom of an aryl or heteroaryl group include -halo, —NO₂, —CN,—R*, —C(R*)═C(R*)₂, —C≡C—R*, —OR*, —SR^(o), —S(O)R^(o), —SO₂R^(o),—SO₃R^(o), —SO₂N(R⁺)₂, —N(R⁺)₂, —NR⁺C(O)R*, —NR⁺C(O)N(R⁺)₂,—NR⁺CO₂R^(o), —O—CO₂R*, —OC(O)N(R⁺)₂, —O—C(O)R*, —CO₂R*, —C(O)—C(O)R*,—C(O)R*, —C(O)N(R⁺)₂, —C(O)N(R⁺)C(═NR⁺)—N(R⁺)₂,—N(R⁺)C(═NR⁺)—N(R⁺)—C(O)R*, —C(═NR⁺)—N(R⁺)₂, —C(═NR⁺)—OR*,—N(R⁺)—N(R⁺)₂, —N(R⁺)C(═NR⁺)—N(R⁺)₂, —NR⁺SO₂R^(o), —NR⁺SO₂N(R⁺)₂,—P(O)(R⁺)₂, —P(O)(OR*)₂, —O—P(O)—OR*, and —P(O)(NR⁺)—N(R⁺)₂; or twoadjacent substituents, taken together with their intervening atoms, forma 5-6 membered unsaturated or partially unsaturated ring having 0-3 ringatoms selected from the group consisting of N, O, and S.

Each R⁺, independently, is hydrogen or an optionally substitutedaliphatic, aryl, heteroaryl, or heterocyclyl group, or two R⁺ on thesame nitrogen atom, taken together with the nitrogen atom, form a 5-8membered aromatic or non-aromatic ring having, in addition to thenitrogen atom, 0-2 ring heteroatoms selected from N, O, and S. Each R*independently is hydrogen or an optionally substituted aliphatic, aryl,heteroaryl, or heterocyclyl group. Each R^(o) is an optionallysubstituted aliphatic or aryl group.

An aliphatic group or a non-aromatic heterocyclic ring may besubstituted with one or more substituents. Examples of suitablesubstituents on the saturated carbon of an aliphatic group or of anon-aromatic heterocyclic ring include, without limitation, those listedabove for the unsaturated carbon of an aryl or heteroaryl group and thefollowing: ═O, ═S, ═C(R*)₂, ═N—N(R*)₂, ═N—OR*, ═N—NHC(O)R*,═N—NHCO₂R^(o), ═N—NHSO₂R^(o), or ═N—R*, where each R* and R^(o) is asdefined above.

Suitable substituents on the nitrogen atom of a non-aromaticheterocyclic ring include —R*, —N(R*)₂, —C(O)R*, —CO₂R*,—C(O)—C(O)R*—C(O)CH₂C(O)R*, —SO₂R*, —SO₂N(R*)₂, —C(═S)N(R⁺)₂,—C(═O—NH)—N(R*)₂, and —NR*SO₂R*; wherein each R* is as defined above.

Unless otherwise stated, structures depicted herein are meant to includecompounds which differ only in the presence of one or more isotopicallyenriched atoms. For example, compounds having the present structureexcept for the replacement of a hydrogen atom by a deuterium or tritium,or the replacement of a carbon atom by a ¹³C- or ¹⁴C-enriched carbon arewithin the scope of the invention.

It will be apparent to one skilled in the art that certain compoundsdescribed herein may exist in tautomeric forms, all such tautomericforms of the compounds being within the scope of the invention. Unlessotherwise stated, structures depicted herein are also meant to includeall stereochemical forms of the structure; i.e., the R and Sconfigurations for each asymmetric center. Therefore, singlestereochemical isomers as well as enantiomeric and diastereomericmixtures of the present compounds are within the scope of the invention.

Any compound capable of inhibiting the enzymatic activity of an Aurorakinase may be used in the methods of the instant invention. Inparticular, Aurora kinase inhibitors include the compounds describedherein, as well as compounds disclosed in, for example, WO 05/111039,US2005/0256102, US2007/0185087, WO 08/021,038, US2008/0045501, WO08/063,525, US2008/0167292, WO 07/113,212, EP1644376, US2005/0032839, WO05/005427, WO 06/070192, WO 06/070198, WO 06/070202, WO 06/070195, WO06/003440, WO 05/002576, WO 05/002552, WO 04/071507, WO 04/058781, WO06/055528, WO 06/055561, WO 05/118544, WO 05/013996, WO 06/036266,US2006/0160874, US2007/0142368, WO 04/043953, WO 07/132,220, WO07/132,221, WO 07/132,228, WO 04/00833 and WO 07/056,164, each of whichis hereby incorporated by reference in its entirety. Also suitable foruse in the methods of the invention are solvated and hydrated forms ofany of these compounds. Also suitable for use in the methods of theinvention are pharmaceutically acceptable salts of any of the compounds,and solvated and hydrated forms of such salts. These Aurora kinaseinhibitors can be prepared in a number of ways well known to one skilledin the art of organic synthesis, including, but not limited to, themethods of synthesis described in detail in the above references.

In some embodiments, the Aurora kinase inhibitor is a compoundrepresented by formula (I):

or a pharmaceutically acceptable salt thereof;

wherein:

-   -   Ring A is a substituted or unsubstituted 5- or 6-membered aryl,        heteroaryl, cycloaliphatic, or heterocyclyl ring;    -   Ring B is a substituted or unsubstituted aryl, heteroaryl,        cycloaliphatic, or heterocyclyl ring;    -   Ring C is a substituted or unsubstituted aryl, heteroaryl,        heterocyclyl, or cycloaliphatic ring;    -   R^(e) is hydrogen, —OR⁵, —N(R⁴)₂, —SR⁵, or a C₁₋₃ aliphatic        optionally substituted with R³ or R⁷;    -   each of R^(x) and R^(y) independently is hydrogen, fluoro, or an        optionally substituted C₁₋₆ aliphatic; or R^(x) and R^(y), taken        together with the carbon atom to which they are attached, form        an optionally substituted 3- to 6-membered cycloaliphatic ring;    -   each R³ independently is selected from the group consisting of        -halo, —OH, —O(C₁₋₃ alkyl), —CN, —N(R⁴)₂, —C(O)(C₁₋₃ alkyl),        —CO₂H, —CO₂(C₁₋₃ alkyl), —C(O)NH₂, and —C(O)NH(C₁₋₃ alkyl);    -   each R⁴ independently is hydrogen or an optionally substituted        aliphatic, aryl, heteroaryl, or heterocyclyl group; or two R⁴ on        the same nitrogen atom, taken together with the nitrogen atom,        form an optionally substituted 5- to 6-membered heteroaryl or 4-        to 8-membered heterocyclyl ring having, in addition to the        nitrogen atom, 0-2 ring heteroatoms selected from N, O, and S;    -   each R⁵ independently is hydrogen or an optionally substituted        aliphatic, aryl, heteroaryl, or heterocyclyl group; and    -   each R⁷ independently is an optionally substituted aryl,        heterocyclyl, or heteroaryl group.

Ring A is a substituted or unsubstituted 5- or 6-membered aryl,heteroaryl, cycloaliphatic, or heterocyclyl ring. Examples of Ring Ainclude furano, dihydrofurano, thieno, dihydrothieno, cyclopenteno,cyclohexeno, 2H-pyrrolo, pyrrolo, pyrrolino, pyrrolidino, oxazolo,thiazolo, imidazolo, imidazolino, imidazolidino, pyrazolo, pyrazolino,pyrazolidino, isoxazolo, isothiazolo, oxadiazolo, triazolo, thiadiazolo,2H-pyrano, 4H-pyrano, benzo, pyridino, piperidino, dioxano, morpholino,dithiano, thiomorpholino, pyridazino, pyrimidino, pyrazino, piperazino,and triazino, any of which groups may be substituted or unsubstituted.Preferred values for Ring A include, without limitation, substituted orunsubstituted rings selected from the group consisting of furano,thieno, pyrrolo, oxazolo, thiazolo, imidazolo, pyrazolo, isoxazolo,isothiazolo, triazolo, benzo, pyridino, pyridazino, pyrimidino, andpyrazino.

Ring A may be substituted or unsubstituted. In some embodiments, eachsubstitutable saturated ring carbon atom in Ring A is unsubstituted oris substituted with ═O, ═S, ═C(R⁵)₂, ═N—N(R⁴)₂, ═N—OR⁵, ═N—NHC(O)R⁵,═N—NHCO₂R⁶, ═N—NHSO₂R⁶, ═N—R⁵ or —R^(b), where R^(b), R⁴, R⁵, and R⁶ areas defined below. Each substitutable unsaturated ring carbon atom inRing A is unsubstituted or substituted with —R^(b). Each substitutablering nitrogen atom in Ring A is unsubstituted or is substituted with—R^(9b), and one ring nitrogen atom in Ring A optionally is oxidized.Each R^(9b) independently is —C(O)R⁵, —C(O)N(R⁴)₂, —CO₂R⁶, —SO₂R⁶,—SO₂N(R⁴)₂, or a C₁₋₄ aliphatic optionally substituted with R³ or R⁷.

Each R^(b) independently is R^(2b), an optionally substituted aliphatic,or an optionally substituted aryl, heterocyclyl, or heteroaryl group; ortwo adjacent R^(b), taken together with the intervening ring atoms, forman optionally substituted fused 4- to 8-membered aromatic ornon-aromatic ring having 0-3 ring heteroatoms selected from the groupconsisting of O, N, and S.

Each R^(2b) independently is -halo, —NO₂, —CN, —C(R⁵)═C(R⁵)₂,—C(R⁵)═C(R⁵)(R¹⁰), —OR⁵, —SR⁶, —S(O)R⁶, —SO₂R⁶, —SO₂N(R⁴)₂, —N(R⁴)₂,—NR⁴C(O)R⁵, —NR⁴C(O)N(R⁴)₂, —NR⁴CO₂R⁶, —O—CO₂R⁵, —OC(O)N(R⁴)₂,—O—C(O)R⁵, —CO₂R⁵, —C(O)—C(O)R⁵, —C(O)R⁵, —C(O)N(R⁴)₂, —C(═NR⁴)—N(R⁴)₂,—C(═NR⁴)—OR⁵, —N(R⁴)—N(R⁴)₂, N(R⁴)C(═NR⁴)—N(R⁴)₂, —N(R⁴)SO₂R⁶,—N(R⁴)SO₂N(R⁴)₂, —P(O)(R⁵)₂, or —P(O)(OR⁵)₂, where the variables R⁴, R⁵,and R⁷ have the values described above; each R⁶ independently is anoptionally substituted aliphatic or aryl group; and each R¹⁰independently is —CO₂R⁵ or —C(O)N(R⁴)₂.

In some embodiments, Ring A is substituted by 0-2 substituents R^(b). Insome such embodiments, each R^(b) independently is C₁₋₃ aliphatic orR^(2b), and each R^(2b) independently is selected from the groupconsisting of -halo, —NO₂, —C(R⁵)═C(R⁵)₂, —C═C—R⁵, —OR⁵, and —N(R⁴)₂. Insome embodiments, each R^(b) independently is selected from the groupconsisting of -halo, C₁₋₃ aliphatic, C₁₋₃ fluoroaliphatic, and —OR⁵,where R⁵ is hydrogen or C₁₋₃ aliphatic. In certain preferredembodiments, Ring A is substituted with 0, 1, or 2 substituents,preferably 0 or 1 substituents, independently selected from the groupconsisting of chloro, fluoro, bromo, methyl, trifluoromethyl, andmethoxy.

In some embodiments, Ring B is a substituted or unsubstituted mono- orbicyclic aryl or heteroaryl ring selected from the group consisting offuranyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl,isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, phenyl,pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolizinyl,indolyl, isoindolyl, indazolyl, benzo[b]furanyl, benzo[b]thienyl,benzimidazolyl, benzthiazolyl, benzoxazolyl, purinyl, quinolyl,isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl,naphthyridinyl, and pteridinyl.

Each substitutable saturated ring carbon atom in Ring B is unsubstitutedor is substituted with ═O, ═S, ═C(R⁵)₂, ═N—N(R⁴)₂, ═N—OR⁵, ═N—NHC(O)R⁵,═N—NHCO₂R⁶, ═N—NHSO₂R⁶, ═N—R⁵ or —R^(c). Each substitutable unsaturatedring carbon atom in Ring B is unsubstituted or substituted with —R^(c).Each substitutable ring nitrogen atom in Ring B is unsubstituted or issubstituted with —R^(9e), and one ring nitrogen atom in Ring Boptionally is oxidized. Each R^(9c) independently is —C(O)R⁵,—C(O)N(R⁴)₂, —CO₂R⁶, —SO₂R⁶, —SO₂N(R⁴)₂, or a C₁₋₄ aliphatic optionallysubstituted with R³ or R⁷. Ring B may be unsubstituted or may besubstituted on any one or more of its component rings, wherein thesubstituents may be the same or different. In some embodiments, Ring Bis substituted with 0-2 independently selected R^(c) and 0-3independently selected R^(2c) or C₁₋₆ aliphatic groups. The variablesR³, R⁴, R⁵, R⁶, and R⁷ are as defined above for Ring A, and R^(c) andR^(2c) are defined below.

Each R^(c) independently is R^(2c), an optionally substituted C₁₋₆aliphatic, or an optionally substituted aryl, heteroaryl, orheterocyclyl group.

Each R^(2c) independently is -halo, —NO₂, —CN, —C(R⁵)═C(R⁵)₂,—C(R⁵)═C(R⁵)(R¹⁰), —C≡C—R⁵, —C≡C—R¹⁰, —OR⁵, —SR⁶, —S(O)R⁶, —SO₂R⁶,—SO₂N(R⁴)₂, —N(R⁴)₂, —NR⁴C(O)R⁵, —NR⁴C(O)N(R⁴)₂, —NR⁴CO₂R⁶, —O—CO₂R⁵,—OC(O)N(R⁴)₂, —O—C(O)R⁵, —CO₂R⁵, —C(O)—C(O)R⁵, —C(O)R⁵, —C(O)N(R⁴)₂,—C(═NR⁴)—N(R⁴)², —C(═NR⁴)—OR⁵, —N(R⁴)—N(R⁴)₂, —N(R⁴)C(═NR⁴)—N(R⁴)₂,—N(R⁴)SO₂R⁶, —N(R⁴)SO₂N(R⁴)₂, —P(O)(R⁵)₂, or —P(O)(OR⁵)₂.

In some embodiments, Ring B is a monocyclic 5- or 6-membered aryl orheteroaryl ring, substituted with 0-2 independently selected R^(c) and0-2 independently selected R^(2c) or C₁₋₆ aliphatic groups. In certainsuch embodiments, Ring B is a substituted or unsubstituted phenyl orpyridyl ring.

In some embodiments, Ring B is substituted with 0-2 substituents R^(c).In some such embodiments, each R^(c) independently is C₁₋₃ aliphatic orR^(2c), and each R^(2c) independently is selected from the groupconsisting of -halo, —NO₂, —C(R⁵)═C(R⁵)₂, —OR⁵, and —N(R⁴)₂. In someembodiments, each R^(c) independently is selected from the groupconsisting of -halo, C₁₋₃ aliphatic, C₁₋₃ haloaliphatic, and —OR⁵, whereR⁵ is hydrogen or C₁₋₃ aliphatic. In certain preferred embodiments, RingB is substituted with 0, 1, or 2 substituents, independently selectedfrom the group consisting of chloro, fluoro, bromo, methyl,trifluoromethyl, and methoxy.

Each substitutable saturated ring carbon atom in Ring C is unsubstitutedor is substituted with ═O, ═S, ═C(R⁵)₂, ═N—N(R⁴)₂, ═N—OR⁵, ═N—NHC(O)R⁵,═N—NHCO₂R⁶, ═N—NHSO₂R⁶, ═N—R⁵ or —R^(d). Each substitutable unsaturatedring carbon atom in Ring C is unsubstituted or substituted with —R^(d).Each substitutable ring nitrogen atom in Ring C is unsubstituted or issubstituted with —R^(9d), and one ring nitrogen atom in Ring Coptionally is oxidized. Each R^(9d) independently is —C(O)R⁵,—C(O)N(R⁴)₂, —CO₂R⁶, —SO₂R⁶, —SO₂N(R⁴)₂, or a C₁₋₄ aliphatic optionallysubstituted with R³ or R⁷. Ring C may be unsubstituted or may besubstituted on any one or more of its component rings, wherein thesubstituents may be the same or different. In some embodiments, Ring Cis substituted with 0-2 independently selected R^(d) and 0-3independently selected R^(2d) or C₁₋₆ aliphatic groups. The variablesR³, R⁴, R⁵, R⁶, and R⁷ are as described above for Rings A and B. Thevariables R^(d) and R^(2d) are described below.

Each R^(d) independently is R^(2d), an optionally substituted aliphatic,or an optionally substituted aryl, heteroaryl, or heterocyclyl group.

Each R^(2d) independently is -halo, —NO₂, —CN, —C(R⁵)═C(R⁵)₂,—C(R⁵)═C(R⁵)₂(R¹⁰), —C≡C—R⁵, —C≡C—R¹⁰, —OR⁵, —SR⁶, —S(O)R⁶, —SO₂R⁶,—SO₂N(R⁴)₂, —N(R⁴)₂, —NR⁴C(O)R⁵, —NR⁴C(O)N(R⁴)₂, —NR⁴CO₂R⁶, —O—CO₂R⁵,—OC(O)N(R⁴)₂, —O—C(O)R⁵, —CO₂R⁵, —C(O)—C(O)R⁵, —C(O)R⁵, —C(O)N(R⁴)₂,—C(═NR⁴)—N(R⁴)₂, —C(═NR⁴)—OR⁵, —N(R⁴)—N(R⁴)₂, —N(R⁴)C═NR⁴)—N(R⁴)₂,—N(R⁴)SO₂R⁶, —N(R⁴)SO₂N(R⁴)₂, —P(O)(R⁵)₂, or —P(O)(OR⁵)₂. Additionally,R^(2d) can be —SO₃R⁵, —C(O)N(R⁴)C(═NR⁴)—N(R⁴)₂ or—N(R⁴)C(═NR⁴)—N(R⁴)—C(O)R⁵.

In some embodiments, Ring C is a monocyclic 5- or 6-membered aryl orheteroaryl ring, which is substituted with 0-2 independently selectedsubstituents R^(d) and 0-2 independently selected R^(2d) or C₁₋₆aliphatic groups. In some such embodiments, Ring C is an optionallysubstituted heteroaryl ring selected from the group consisting ofpyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, andoxazolyl. In some other embodiments, Ring C is a substituted orunsubstituted phenyl ring. In some embodiments, Ring C is a monocyclic5- or 6-membered aryl or heteroaryl ring, which is substituted with 0,1, or 2 substituents R^(d), as defined above.

In some other embodiments, Ring C is a monocyclic 5- or 6-memberedheterocyclyl or cycloaliphatic ring, which is substituted with 0-2independently selected substituents R^(d) and 0-2 independently selectedR^(2d) or C₁₋₆ aliphatic groups.

In some embodiments, the Aurora kinase inhibitor is a compoundrepresented by formula (II):

or a pharmaceutically acceptable salt thereof;

wherein:

-   -   R^(e) is hydrogen or a C₁₋₃ aliphatic optionally substituted        with R³ or R⁷;    -   Ring A is substituted with 0-3 R^(b);        -   each R^(b) independently is selected from the group            consisting of C₁₋₆ aliphatic, R^(2b), R^(7b), -T¹-R^(2b),            and -T¹-R^(7b);        -   each R^(2b) independently is -halo, —NO₂, —CN,            —C(R⁵)═C(R⁵)₂, —OR⁵, —SR⁶, —S(O)R⁶, —SO₂R⁶, —SO₂N(R⁴)₂,            —N(R⁴)₂, —NR⁴C(O)R⁵, —NR⁴C(O)N(R⁴)₂, —NR⁴CO₂R⁶, —O—CO₂R⁵,            —OC(O)N(R⁴)₂, —O—C(O)R⁵, —CO₂R⁵, —C(O)—C(O)R⁵, —C(O)R⁵,            —C(O)N(R⁴)₂, —C(═NR⁴)—N(R⁴)₂, —C(═NR⁴)—OR⁵, —N(R⁴)—N(R⁴)₂,            —N(R⁴)C(═NR⁴)—N(R⁴)₂, —N(R⁴)SO₂R⁶, —N(R⁴)SO₂N(R⁴)₂,            —P(O)(R⁵)₂, or —P(O)(OR⁵)₂;        -   each R^(7b) independently is an optionally substituted aryl,            heterocyclyl, or heteroaryl group;    -   Ring B is substituted with 0-2 independently selected R^(c) and        0-2 independently selected R^(2c) or C₁₋₆ aliphatic groups;        -   each R^(c) independently is selected from the group            consisting of C₁₋₆ aliphatic, R^(2c), R^(7c), -T¹-R^(2c),            and -T¹-R^(7c);        -   each R^(2c) independently is -halo, —NO₂, —CN,            —C(R⁵)═C(R⁵)₂, —OR⁵, —SR⁶, —S(O)R⁶, —SO₂R⁶, —SO₂N(R⁴)₂,            —N(R⁴)₂, —NR⁴C(O)R⁵, —NR⁴C(O)N(R⁴)₂, —NR⁴CO₂R⁶, —O—CO₂R⁵,            —OC(O)N(R⁴)₂, —O—C(O)R⁵, —CO₂R⁵, —C(O)—C(O)R⁵, —C(O)R⁵,            —C(O)N(R⁴)₂, —C(═NR⁴)—N(R⁴)₂, —C(═NR⁴)—OR⁵, —N(R⁴)—N(R⁴)₂,            —N(R⁴)C(═NR⁴)—N(R⁴)₂, —N(R⁴)SO₂R⁶, —N(R⁴)SO₂N(R⁴)₂,            —P(O)(R⁵)₂, or —P(O)(OR⁵)₂;        -   each R^(7c) independently is an optionally substituted aryl,            heterocyclyl, or heteroaryl group;    -   T¹ is a C₁₋₆ alkylene chain optionally substituted with R³ or        R^(3b), wherein T¹ or a portion thereof optionally forms part of        a 3- to 7-membered ring;    -   Ring C is substituted with 0-2 independently selected R^(d) and        0-3 independently selected R^(2d) or C₁₋₆ aliphatic groups;        -   each R^(d) independently is selected from the group            consisting of C₁₋₆ aliphatic, R^(2d), R^(7d), -T²-R^(2d),            -T²-R^(7d), —V-T³-R^(2d), and —V-T³-R^(7d);        -   T² is a C₁₋₆ alkylene chain optionally substituted with R³            or R^(3b), wherein the alkylene chain optionally is            interrupted by —C(R⁵)═C(R⁵)—, —C≡C—, —O—, —S—, —S(O)—,            —S(O)₂—, —SO₂N(R⁴)—, —N(R⁴)—, —N(R⁴)C(O)—, —NR⁴C(O)N(R⁴)—,            —N(R⁴)CO₂—, —C(O)N(R⁴)—, —C(O)—, —C(O)—C(O)—, —CO₂—,            —OC(O)—, —OC(O)O—, —OC(O)N(R⁴)—, —N(R⁴)—N(R⁴)—, —N(R⁴)SO₂—,            or —SO₂N(R⁴)—, and wherein T² or a portion thereof            optionally forms part of a 3-7 membered ring;        -   T³ is a C₁₋₆ alkylene chain optionally substituted with R³            or R^(3b), wherein the alkylene chain optionally is            interrupted by —C(R⁵)═C(R⁵)—, —O—, —S—, —S(O)—, —S(O)₂—,            —SO₂N(R⁴)—, —N(R⁴)—, —N(R⁴)C(O)—, —NR⁴C(O)N(R⁴)—,            —N(R⁴)CO₂—, —C(O)N(R⁴)—, —C(O)—, —C(O)—C(O)—, —CO₂—,            —OC(O)—, —OC(O)O—, —OC(O)N(R⁴)—, —N(R⁴)—N(R⁴)—, —N(R⁴)SO₂—,            or —SO₂N(R⁴)—, and wherein T³ or a portion thereof            optionally forms part of a 3-7 membered ring;        -   V is —C(R⁵)═C(R⁵)—, —O—, —S—, —S(O)—, —S(O)₂—, —SO₂N(R⁴)—,            —N(R⁴)—, —N(R⁴)C(O)—, —NR⁴C(O)N(R⁴)—, —N(R⁴)CO₂—,            —C(O)N(R⁴)—, —C(O)—, —C(O)—C(O)—, —CO₂—, —OC(O)—, —OC(O)O—,            —OC(O)N(R⁴)—, —C(NR⁴)═N—, —C(OR⁵)═N—, —N(R⁴)—N(R⁴)—,            —N(R⁴)SO₂—, —N(R⁴)SO₂N(R⁴)—, —P(O)(R⁵)—, —P(O)(OR⁵)—O—,            —P(O)—O—, or —P(O)(NR⁵)—N(R⁵)—;        -   R^(2d) is -halo, —NO₂, —CN, —C(R⁵)═C(R⁵)₂, —C═C—R⁵, —OR⁵,            —SR⁶, —S(O)R⁶, —SO₂R⁶, —SO₂N(R⁴)₂, —N(R⁴)₂, —NR⁴C(O)R⁵,            —NR⁴C(O)N(R⁴)₂, —NR⁴CO₂R⁶, —O—CO₂R⁵, —OC(O)N(R⁴)₂,            —O—C(O)R⁵, —CO₂R⁵, —C(O)—C(O)R⁵, —C(O)R⁵, —C(O)N(R⁴)₂,            —C(═NR⁴)—N(R⁴)₂, —C(═NR⁴)—OR⁵, —N(R⁴)—N(R⁴)₂,            —N(R⁴)C(═NR⁴)—N(R⁴)₂, —N(R⁴)SO₂R⁶, —N(R⁴)SO₂N(R⁴)₂,            —P(O)(R⁵)₂, or —P(O)(OR⁵)₂; and        -   each R^(7d) independently is an optionally substituted aryl,            heterocyclyl, or heteroaryl group.    -   each R³ independently is selected from the group consisting of        -halo, —OH, —O(C₁₋₃ alkyl), —CN, —N(R⁴)₂, —C(O)(C₁₋₃ alkyl),        —CO₂H, —CO₂(C₁₋₃ alkyl), —C(O)NH₂, and —C(O)NH(C₁₋₃ alkyl);    -   each R^(3b) independently is a C₁₋₃ aliphatic optionally        substituted with R³ or R⁷, or two substituents R^(3b) on the        same carbon atom, taken together with the carbon atom to which        they are attached, form a 3- to 6-membered carbocyclic ring;    -   each R⁴ independently is hydrogen or an optionally substituted        aliphatic, aryl, heteroaryl, or heterocyclyl group; or two R⁴ on        the same nitrogen atom, taken together with the nitrogen atom,        form an optionally substituted 5- to 8-membered heteroaryl or        heterocyclyl ring having, in addition to the nitrogen atom, 0-2        ring heteroatoms selected from N, O, and S;    -   each R⁵ independently is hydrogen or an optionally substituted        aliphatic, aryl, heteroaryl, or heterocyclyl group;    -   each R⁶ independently is an optionally substituted aliphatic or        aryl group; and    -   each R⁷ independently is an optionally substituted aryl,        heterocyclyl, or heteroaryl group.

Table 1 provides the chemical names for specific examples of compoundsof formula (II).

TABLE 1 Examples of Compounds of Formula (II) II-1:4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-N-(2-methylamino-ethyl)-benzamide II-2:N-(2-Amino-ethyl)-4-[9-chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido-[4,5-e]azepin-2-ylamino]-N-methyl-benzamide II-3:4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-N-methyl-N-(2-methylamino-ethyl)-benzamide II-4:4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-N-(2-dimethylamino-ethyl)-benzamide II-5:4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-N-(2-dimethylamino-ethyl)-N-methyl-benzamide II-6:4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-N-(3-dimethylamino-propyl)-benzamide II-7:4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-N-(3-dimethylamino-propyl)-N-methyl-benzamide II-8:{4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-phenyl}-piperazin-1-yl-methanone II-9:{4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-phenyl}-(4-methyl-piperazin-1-yl)-methanone II-10:{4-[9-Chloro-7-(2-chloro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-phenyl}-(4-methyl-piperazin-1-yl)-methanone II-11:[4-(9-Chloro-7-o-tolyl-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino)-phenyl]-(4-methyl-piperazin-1-yl)-methanone II-12:{4-[9-Chloro-7-(2-methoxy-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-phenyl}-(4-methyl-piperazin-1-yl)-methanone II-13:{4-[9-Chloro-7-(4-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-phenyl}-(4-methyl-piperazin-1-yl)-methanone II-14:{4-[7-(2-Fluoro-phenyl)-9-methyl-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-phenyl}-(4-methyl-piperazin-1-yl)-methanone II-15:2-{3-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-phenyl}-1-(4-methyl-piperazin-1-yl)-ethanone II-16:4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-N-piperidin-4-yl-benzamide II-17:(4-Amino-piperidin-1-yl)-{4-[9-chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-phenyl}-methanone II-18:{4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-phenyl}-(4-dimethylamino-piperidin-1-yl)-methanone II-19:4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-N-[3-(4-methyl-piperazin-1-yl)-propyl]-benzamide II-20:4-[9-Chloro-7-(2-chloro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-N-[3-(4-methyl-piperazin-1-yl)-propyl]-benzamide II-21:4-(9-Chloro-7-o-tolyl-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino)-N-[3-(4-methyl-piperazin-1-yl)-propyl]-benzamide II-22:4-[9-Chloro-7-(2-methoxy-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-N-[3-(4-methyl-piperazin-1-yl)-propyl]-benzamide II-23:4-[9-Chloro-7-(4-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-N-[3-(4-methyl-piperazin-1-yl)-propyl]-benzamide II-24:4-[7-(2-Fluoro-phenyl)-9-methyl-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-N-[3-(4-methyl-piperazin-1-yl)-propyl]-benzamide II-25:2-{3-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-phenyl}-N-[3-(4-methyl-piperazin-1-yl)-propyl]-acetamide II-26:{4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-phenyl}-morpholin-4-yl-methanone II-27:4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-N,N-bis-(2-hydroxy-ethyl)-benzamide II-28:{4-[9-Chloro-7-(2-chloro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-phenyl}-morpholin-4-yl-methanone II-29:4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-N-(2-morpholin-4-yl-ethyl)-benzamide II-30:4-[9-Chloro-7-(2-chloro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-N-(2-morpholin-4-yl-ethyl)-benzamide II-31:4-(9-Chloro-7-o-tolyl-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino)-N-(2-morpholin-4-yl-ethyl)-benzamide II-32:4-[9-Chloro-7-(2-methoxy-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-N-(3-morpholin-4-yl-propyl)-benzamide II-33:4-[9-Chloro-7-(4-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-N-(2-morpholin-4-yl-ethyl)-benzamide II-34:4-[9-Chloro-7-(2-chloro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-2-hydroxy-N-(2-morpholin-4-yl-ethyl)-benzamide II-35:[9-Chloro-7-(2-chloro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl]-pyridin-2-yl-amine II-36:[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl]-(3,5-dichloro-phenyl)-amine II-37:[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl]-(4-methoxy-phenyl)-amine II-38:[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl]-(4-ethoxy-phenyl)-amine II-39:[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl]-(3-methoxy-phenyl)-amine II-40:[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl]-(2-methoxy-phenyl)-amine II-41:[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl]-(4-chloro-phenyl)-amine II-42:[9-Chloro-7-(2-chloro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl]-(4-chloro-phenyl)-amine II-43:[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl]-(3-chloro-phenyl)-amine II-44:[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl]-(2-chloro-phenyl)-amine II-45:4-[9-Chloro-7-(2-chloro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-phenol II-46:[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl]-(4-morpholin-4-yl-phenyl)-amine II-47:[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl]-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine II-48:[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl]-(4-pyridin-4-ylmethyl-phenyl)-amine II-49:4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-benzonitrile II-50:[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl]-(4-nitro-phenyl)-amine II-51:4-[7-(2-Fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-benzoic acid II-52:4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-benzoic acid II-53:4-[9-Chloro-7-(2-chloro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-benzoic acid II-54:4-(9-Chloro-7-o-tolyl-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino)-benzoic acid II-55:4-[9-Chloro-7-(2-methoxy-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-benzoic acid II-56:4-[9-Chloro-7-(4-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-benzoic acid II-57:4-[9-Fluoro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-benzoic acid II-58:4-[7-(2-Fluoro-phenyl)-9-methyl-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-benzoic acid II-59:4-[10-Fluoro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-benzoic acid II-60:4-[10-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-benzoic acid II-61:4-[10-Bromo-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-benzoic acid II-62:4-[7-(2-Fluoro-phenyl)-10-methoxy-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-benzoic acid II-63:4-[9-Chloro-7-(2-chloro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-benzamide II-64:3-[9-Chloro-7-(2-chloro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-benzamide II-65:{3-[9-Chloro-7-(2-chloro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-phenyl}-acetic acid II-66:2-{3-[9-Chloro-7-(2-chloro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-phenyl}-acetamide II-67:4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-benzenesulfonic acid II-68:4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-benzenesulfonamide II-69:4-[9-Chloro-7-(2-chloro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-N-(5-methyl-isoxazol-3-yl)-benzenesulfonamide II-70:[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl]-(4-trifluoromethanesulfonyl-phenyl)-amine II-71:[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl]-(3,4-dimethoxy-phenyl)-amine II-72:[9-Chloro-7-(2-fluoro-phenyl)-6,7-dihydro-5H-benzo[c]pyrimido-[4,5-e]azepin-2-yl]-(3,4-dimethoxy-phenyl)-amine II-73:[9-Chloro-7-(2-chloro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl]-(3,4-dimethoxy-phenyl)-amine II-74:(9-Chloro-7-o-tolyl-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl)-(3,4-dimethoxy-phenyl)-amine II-75:(3,4-Dimethoxy-phenyl)-[7-(2-fluoro-phenyl)-9-methyl-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl]-amine II-76:(3,4-Dimethoxy-phenyl)-[7-(2-fluoro-phenyl)-9-isopropyl-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl]-amine II-77:(3,4-Dimethoxy-phenyl)-[10-fluoro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl]-amine II-78:[10-Bromo-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl]-(3,4-dimethoxy-phenyl)-amine II-79:(3,4-Dimethoxy-phenyl)-[7-(2-fluoro-phenyl)-10-trifluoromethyl-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl]-amine II-80:(3,4-Dimethoxy-phenyl)-[7-(2-fluoro-phenyl)-10-methyl-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl]-amine II-81:(3,4-Dimethoxy-phenyl)-[7-(2-fluoro-phenyl)-10-methoxy-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl]-amine II-82:(3,4-Dimethoxy-phenyl)-[7-(2-fluoro-phenyl)-11-methyl-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl]-amine II-83:[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl]-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-amine II-84:[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl]-(4-fluoro-3-methoxy-phenyl)-amine II-85:4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-2-hydroxy-benzoic acid II-86:4-[9-Chloro-7-(2-chloro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-2-hydroxy-benzoic acid II-87:[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl]-(3,4-dichloro-phenyl)-amine II-88:[9-Chloro-7-(2-chloro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl]-(3,5-dimethoxy-phenyl)-amine II-89:[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl]-(3,5-dimethyl-phenyl)-amine II-90:[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl]-phenyl-amine II-91:4-[9-Chloro-7-(2,5-difluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-benzoic acid II-92:4-[9-Chloro-7-(2,3-difluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-benzoic acid II-93:(3-Dimethylamino-pyrrolidin-1-yl)-{4-[7-(2-fluoro-phenyl)-9-methoxy-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-phenyl}-methanone II-94:4-[9-Chloro-7-(2,5-dimethoxy-phenyl)-5H-benzo[c]pyrimido-[4,5-e]azepin-2-ylamino]-benzoic acid II-95:4-[7-(2-Fluoro-phenyl)-9-methoxy-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-N,N-bis-(2-hydroxy-ethyl)-benzamide II-96:4-[9-Chloro-7-(2,4-difluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-benzoic acid II-97:4-[9-Chloro-7-(2,4-difluoro-phenyl)-7H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-benzoic acid II-98:{4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-phenyl}-(3-dimethylamino-azetidin-1-yl)-methanone II-99:4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-N-methyl-N-(1-methyl-pyrrolidin-3-yl)-benzamide II-100:{4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-phenyl}-(3-dimethylamino-pyrrolidin-1-yl)-methanone II-101:4-[9-Chloro-7-(2,4-dimethoxy-phenyl)-5H-benzo[c]pyrimido-[4,5-e]azepin-2-ylamino]-benzoic acid II-102:{4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-phenyl}-(3-methylamino-pyrrolidin-1-yl)-methanone II-103:(3-Amino-pyrrolidin-1-yl)-{4-[9-chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-phenyl}-methanone II-104:4-[9-Chloro-7-(2,3-difluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-benzoic acid methyl ester II-105:4-[9-Chloro-7-(2,5-difluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-benzoic acid methyl ester II-106:{4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-phenyl}-phosphonic acid II-107:N-{4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-phenyl}-methanesulfonamide II-108:N-{4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-phenyl}-N-methyl-acetamide II-109:2-{4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-benzoylamino}-succinic acid II-110:[9-Chloro-7-(2-fluoro-phenyl)-4-methyl-5H-benzo[c]pyrimido-[4,5-e]azepin-2-yl]-(3,4-dimethoxy-phenyl)-amine II-111:{4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-phenyl}-(3,5-dimethyl-piperazin-1-yl)-methanone II-112:1-{4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-benzoyl}-pyrrolidine-2-carboxylic acid II-113:{4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-phenyl}-(3-methyl-piperazin-1-yl)-methanone II-114:[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl]-[4-(2H-tetrazol-5-yl)-phenyl]-amine II-115:N-{4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-phenyl}-acetamide II-116:5-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-2-fluoro-benzoic acid II-117:N-(3-Amino-propyl)-4-[9-chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-N-methyl-benzamide II-118:2-{4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-benzoylamino}-propionic acid II-119:5-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-pyridine-2-carboxylic acid II-120:2-{4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-phenyl}-N-(2-morpholin-4-yl-ethyl)-acetamide II-121:5-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-2-methoxy-benzoic acid II-122:5-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-2-methyl-benzoic acid II-123:6-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-nicotinic acid II-124:4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-N-(2-morpholin-4-yl-ethyl)-benzenesulfonamide II-125:2-Chloro-5-[9-chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido-[4,5-e]azepin-2-ylamino]-benzoic acid II-126:{4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-phenyl}-acetic acid II-127:4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-2-trifluoromethyl-benzoic acid II-128:4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-N-methyl-N-(1-methyl-piperidin-4-yl)-benzamide II-129:N-(3-Amino-propyl)-4-[9-chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-benzamide II-130:4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-N-(3-methylamino-propyl)-benzamide II-131:N-(2-Amino-2-methyl-propyl)-4-[9-chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-benzamide II-132:2-(3,4-Dimethoxy-phenylamino)-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepine-10-carboxylic acid II-133:4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-2-methyl-benzoic acid II-134:2-Chloro-4-[9-chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido-[4,5-e]azepin-2-ylamino]-benzoic acid II-135:4-[9-Chloro-7-(2,6-difluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-benzoic acid II-136:4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-2-fluoro-benzoic acid II-137:4-[7-(2-Fluoro-phenyl)-9-methoxy-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-benzoic acid II-138:(3,4-Dimethoxy-phenyl)-[7-(2-fluoro-phenyl)-9-methoxy-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl]-amine II-139:[9,10-Dichloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl]-(3,4-dimethoxy-phenyl)-amine II-140:4-[9,10-Dichloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-benzoic acid II-141:4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-2-methoxy-benzoic acid II-142:N-(2-Amino-ethyl)-4-[9-chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido-[4,5-e]azepin-2-ylamino]-benzamide II-143:4-(9-Chloro-7-phenyl-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino)-benzoic acid II-144:[7-(2-Bromo-phenyl)-9-chloro-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl]-(3,4-dimethoxy-phenyl)-amine II-145:2-{4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-phenyl}-1-(4-methyl-piperazin-1-yl)-ethanone II-146:3-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-benzoic acid II-147:4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-N-[2-(1H-imidazol-4-yl)-ethyl]-benzamide II-148:4-[7-(2-Fluoro-phenyl)-9-methyl-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-N-(2-morpholin-4-yl-ethyl)-benzamide II-149:{3-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-phenyl}-acetic acid II-150:4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-N-(2-pyridin-4-yl-ethyl)-benzamide II-151:4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-N-(2-pyridin-3-yl-ethyl)-benzamide II-152:(9-Chloro-7-phenyl-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl)-(3,4-dimethoxy-phenyl)-amine II-153:4-[7-(2-Fluoro-phenyl)-10-methyl-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-benzoic acid II-154:(3,4-Dimethoxy-phenyl)-[7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido-[4,5-e]azepin-2-yl]-amine II-155:4-[9-Chloro-7-(4-methoxy-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-benzoic acid II-156:4-[9-Chloro-7-(3-methoxy-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-benzoic acid II-157:4-[9-Chloro-7-(3-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-N-[3-(4-methyl-piperazin-1-yl)-propyl]-benzamide II-158:4-[9-Chloro-7-(3-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-N-(2-morpholin-4-yl-ethyl)-benzamide II-159:{4-[9-Chloro-7-(3-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-phenyl}-(4-methyl-piperazin-1-yl)-methanone II-160:4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-N-methyl-N-(2-pyridin-2-yl-ethyl)-benzamide II-161:4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-N-(2-pyridin-2-yl-ethyl)-benzamide II-162:4-[9-Chloro-7-(3-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-benzoic acid II-163:[3-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-phenyl}-(4-methyl-piperazin-1-yl)-methanone II-164:9-Chloro-7-(2-fluorophenyl)-N-{4-[(4-pyridin-2-ylpiperazin-1-yl)carbonyl]phenyl}-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-165:9-Chloro-7-(2-fluorophenyl)-N-(4-{[4-(2-morpholin-4-yl-2-oxoethyl)piperazin-1-yl]carbonyl}phenyl)-5H-pyrimido-[5,4-d][2]benzazepin-2-amine II-166:9-Chloro-7-(2-fluorophenyl-N-(4-{[4-(2-furoyl)piperazin-1-yl]carbonyl}phenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-167:Benzyl-4-(4-{[9-chloro-7-(2-fluorophenyl)-5H-pyrimido-[5,4-d][2]benzazepin-2-yl]amino}benzoyl)piperazine-1-carboxylate II-168:Ethyl-4-(4-{[9-chloro-7-(2-fluorophenyl)-5H-pyrimido-[5,4-d][2]benzazepin-2-yl]amino}benzoyl)piperazine-1-carboxylate II-169:2-[4-(4-{[9-Chloro-7-(2-fluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}benzoyl)piperazin-1-yl]benzoic acid II-170:2-[4-(4-{[9-Chloro-7-(2-fluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}benzoyl)piperazin-1-yl]-N-isopropylacetamide II-171:9-Chloro-7-(2-fluorophenyl)-N-(4-{[4-(2-pyrrolidin-1-ylethyl)piperazin-1-yl]carbonyl}phenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-172:N-[2-(aminocarbonyl)phenyl]-4-{[9-chloro-7-(2-fluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}benzamide II-173:9-Chloro-7-(2-fluorophenyl)-N-{4-[(4-pyrimidin-2-ylpiperazin-1-yl)carbonyl]phenyl}-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-174:4-{[9-Chloro-7-(2-chloro-6-fluorophenyl)-5H-pyrimido-[5,4-d][2]benzazepin-2-yl]amino}benzoic acid II-175:9-Chloro-7-(2,6-difluorophenyl)-N-{4-[(3,5-dimethylpiperazin-1-yl)carbonyl]phenyl}-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-176:9-Chloro-7-(2,6-difluorophenyl)-N-(4-{[3-(dimethylamino)pyrrolidin-1-yl]carbonyl}phenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-177:9-Chloro-N-{4-[(3,5-dimethylpiperazin-1-yl)carbonyl]phenyl}-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-178:9-Chloro-N-(4-{[3-(dimethylamino)pyrrolidin-1-yl]carbonyl}phenyl)-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-179:9-Chloro-N-(4-{[3-(dimethylamino)azetidin-1-yl]carbonyl}phenyl)-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-180:9-Chloro-7-(2,6-difluorophenyl)-N-(4-{[3-(dimethylamino)azetidin-1-yl]carbonyl}phenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-181:{4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-phenyl}-[4-(3-piperidin-1-yl-propyl)-piperazin-1-yl]-methanoneII-182:{4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-phenyl}-[4-(2-piperidin-1-yl-ethyl)-piperazin-1-yl]-methanoneII-183:{4-[9-Chloro-7-(2,6-difluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-phenyl}-(4-dimethylamino-piperidin-1-yl)-methanone II-184:{4-[9-Chloro-7-(2,6-difluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-phenyl}-(4-methyl-piperazin-1-yl)-methanone II-185:4-[9-Chloro-7-(2,6-difluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-N-(3-dimethylamino-propyl)-N-methyl-benzamide II-186:{4-[9-Chloro-7-(2-fluoro-6-methoxy-phenyl)-5H-benzo[c]pyrimido-[4,5-e]azepin-2-ylamino]-phenyl}-(4-dimethylamino-piperidin-1-yl)-methanone II-187:{4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-phenyl}-[4-(2-dipropylamino-ethyl)-piperazin-1-yl]-methanoneII-188:{4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-phenyl}-[4-(3-pyrrolidin-1-yl-propyl)-piperazin-1-yl]-methanone II-189:{4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-phenyl}-[4-(2-morpholin-4-yl-ethyl)-piperazin-1-yl]-methanoneII-190:4-[9-Chloro-7-(2-fluoro-6-methoxy-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-benzoic acid II-191:{4-[9-Chloro-7-(2,6-difluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-phenyl)-(3(S)-methyl-piperazin-1-yl)-methanone II-192:(3-Amino-azetidin-1-yl)-{4-[9-chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-phenyl}-methanone II-193:{4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-phenyl}-(3-dimethylaminomethyl-azetidin-1-yl)-methanone II-194:{4-[9-Chloro-7-(2,6-difluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-phenyl}-(3(R)-methyl-piperazin-1-yl)-methanone II-195:{4-[9-Chloro-7-(2,6-difluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-phenyl}-piperazin-1-yl-methanone II-196:(3-Amino-pyrrolidin-1-yl)-{4-[9-chloro-7-(2,6-difluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-phenyl}-methanone II-197:{4-[9-Chloro-7-(2,6-difluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-phenyl}-(3-methylamino-pyrrolidin-1-yl)-methanone II-198:4-[9-Chloro-7-(2,6-difluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-N-methyl-N-(3-methylamino-propyl)-benzamide II-199:{4-[9-Chloro-7-(2-fluoro-6-methoxy-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-phenyl}-(3-methylamino-pyrrolidin-1-yl)- methanoneII-200:4-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-cyclohexanecarboxylic acid II-201:9-chloro-N-(4-{[4-(2-ethoxyphenyl)piperazin-1-yl]carbonyl}phenyl)-7-(2-fluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-202:N-[amino(imino)methyl]-4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}benzamide II-203:3-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}benzoic acid II-204:9-chloro-7-(2,6-difluorophenyl)-N-(3-{[3-(dimethylamino)azetidin-1-yl]carbonyl}phenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-205:9-chloro-7-(2,6-difluorophenyl)-N-(3-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-206:9-chloro-7-(2,6-difluorophenyl)-N-(3-{[3-(dimethylamino)pyrrolidin-1-yl]carbonyl}phenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-207:N-[2-(aminomethyl)-1,3-benzoxazol-5-yl]-9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-208:9-chloro-N-[4-({4-[3-(diethylamino)propyl]piperazin-1-yl}carbonyl)phenyl]-7-(2-fluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-209:9-chloro-N-[4-({4-[2-(diethylamino)ethyl]piperazin-1-yl}carbonyl)phenyl]-7-(2-fluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-210:9-chloro-N-[4-({4-[3-(dimethylamino)propyl]piperazin-1-yl}carbonyl)phenyl]-7-(2-fluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-211:9-chloro-7-(2-fluorophenyl)-N-[4-({4-[(1-methylpiperidin-3-yl)methyl]piperazin-1-yl}carbonyl)phenyl]-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-212:9-chloro-7-(2,6-difluorophenyl)-N-(4-nitrophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-213:9-chloro-N-(3-chloro-4-{[4-(2-pyrrolidin-1-ylethyl)piperazin-1-yl]carbonyl}phenyl)-7-(2-fluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-214:9-chloro-N-{3-chloro-4-[(3-methylpiperazin-1-yl)carbonyl]phenyl}-7-(2-fluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-215:9-chloro-N-(3-chloro-4-{[3-(dimethylamino)pyrrolidin-1-yl]carbonyl}phenyl)-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-216:9-chloro-N-{3-chloro-4-[(3-methylpiperazin-1-yl)carbonyl]phenyl}-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-217:N-[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]benzene-1,4-diamine II-218: methyl2-chloro-4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}benzoate II-219:1-(4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}benzoyl)piperazine-2-carboxylic acid II-220:9-chloro-7-(2,6-difluorophenyl)-N-(4-{[4-(methylamino)piperidin-1-yl]carbonyl}phenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-221:N-{4-[(3-aminopiperidin-1-yl)carbonyl]phenyl}-9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-222:9-chloro-7-(2,6-difluorophenyl)-N-{3-[(3,5-dimethylpiperazin-1-yl)carbonyl]phenyl}-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-223:4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-N-[[4-(dimethylamino)piperidin-1- yl](imino)methyl]benzamideII-224:4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-N-[imino(piperazin-1-yl)methyl]benzamide II-225:4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-N-[3-(dimethylamino)propyl]-N-methylbenzamide II-226:3-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-N-[3-(dimethylamino)propyl]-N-methylbenzamide II-227:9-chloro-N-(3-{[3-(dimethylamino)azetidin-1-yl]carbonyl}phenyl)-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-228:9-chloro-N-{3-[(3,5-dimethylpiperazin-1-yl)carbonyl]phenyl}-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-229:9-chloro-N-(3-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-230:N-(4-{[3-(aminomethyl)azetidin-1-yl]carbonyl}phenyl)-9-chloro-7-(2-fluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-231:9-chloro-N-(3-{[3-(dimethylamino)pyrrolidin-1-yl]carbonyl}phenyl)-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-232:9-chloro-7-(2-fluoro-6-methoxyphenyl)-N-{4-[(3-methylpiperazin-1-yl)carbonyl]phenyl}-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-233:9-chloro-7-(2-fluoro-6-methoxyphenyl)-N-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-234:9-chloro-7-(2,6-difluorophenyl)-N-(4-{[3-(methylamino)azetidin-1-yl]carbonyl}phenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-235:9-chloro-7-(2-fluoro-6-methoxyphenyl)-N-(4-{[3-(methylamino)azetidin-1-yl]carbonyl}phenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-236:4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}benzonitrile II-237:4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-N-[[3-(dimethylamino)pyrrolidin-1- yl](imino)methyl]benzamideII-238:4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-N-[(3,5-dimethylpiperazin-1-yl)(imino)methyl]benzamide II-239:N-{4-[(4-aminopiperidin-1-yl)carbonyl]phenyl}-9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-240:N-{4-[(3-aminopyrrolidin-1-yl)carbonyl]phenyl}-9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-241:N-{4-[(4-aminopiperidin-1-yl)carbonyl]phenyl}-9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-242:9-chloro-7-(2-fluoro-6-methoxyphenyl)-N-(4-{[4-(methylamino)piperidin-1-yl]carbonyl}phenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-243:9-chloro-7-(2-fluoro-6-methoxyphenyl)-N-[4-(piperazin-1-ylcarbonyl)phenyl]-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-244:9-chloro-7-(2,6-difluorophenyl)-N-{4-[[4-(dimethylamino)piperidin-1-yl](imino)methyl]phenyl}-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-245:N-(4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}phenyl)guanidine II-246:4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-N-methyl-N-[2-(methylamino)ethyl]benzamide II-247:4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-N-[2-(dimethylamino)ethyl]-N-methylbenzamide II-248: methyl4-(4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}benzoyl)piperazine-2-carboxylate II-249:2-[(4-carboxyphenyl)amino]-7-(2-fluorophenyl)-5H-pyrimido[5,4-d][2]benzazepine-9-carboxylic acid II-250:9-chloro-7-(2,6-difluorophenyl)-N-{4-[[3-(dimethylamino)pyrrolidin-1-yl](imino)methyl]phenyl}-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-251:9-chloro-7-(2,6-difluorophenyl)-N-{4-[(3,5-dimethylpiperazin-1-yl)(imino)methyl]phenyl}-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-252:N-(2-aminoethyl)-4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-N-methylbenzamide II-253:9-chloro-7-(2,6-difluorophenyl)-N-(4-{[3-(methylamino)piperidin-1-yl]carbonyl}phenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-254:4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-N-methyl-N-[2- (methylamino)ethyl]benzamideII-255: 4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-N-[2-(dimethylamino)ethyl]-N-methylbenzamide II-256:7-(2-fluorophenyl)-2-[(3-methoxyphenyl)amino]-5H-pyrimido[5,4-d][2]benzazepine-9-carboxylic acid II-257:N-(3-aminopropyl)-4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-N-methylbenzamide II-258:2-chloro-5-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}benzoic acid II-259:4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-N-[[3-(dimethylamino)azetidin-1-yl](imino)methyl]benzamideII-260:N-(2-amino-2-methylpropyl)-4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}benzamide II-261:4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-N-methyl-N-[3- (methylamino)propyl]benzamideII-262:N-{4-[(3-aminopiperidin-1-yl)carbonyl]phenyl}-9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-263:9-chloro-7-(2-fluoro-6-methoxyphenyl)-N-(4-{[3-(methylamino)piperidin-1-yl]carbonyl}phenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-264:N-(3-aminopropyl)-4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-N-methylbenzamide II-265:N-(2-aminoethyl)-4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-N-methylbenzamide II-266:4-(4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}benzoyl)piperazine-2-carboxylic acid II-267:9-chloro-7-(2,6-difluorophenyl)-N-{4-[[3-(dimethylamino)azetidin-1-yl](imino)methyl]phenyl}-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-268:9-chloro-7-(2,6-difluorophenyl)-N-(4-{imino[3-(methylamino)pyrrolidin-1-yl]methyl}phenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-269:9-chloro-N-(4-chloro-3-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-270:9-chloro-7-(2,6-difluorophenyl)-N-[4-(5,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl)phenyl]-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-271:N-[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]-N′-pyrimidin-2-ylbenzene-1,4-diamine II-272:4-{[9-(3-aminoprop-1-yn-1-yl)-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}benzoic acid II-273:9-bromo-7-(2,6-difluorophenyl)-N-(3-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-274:4-{[9-bromo-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}benzoic acid II-275:7-(2,6-difluorophenyl)-N-(3-methoxyphenyl)-9-(3-pyrrolidin-1-ylprop-1-yn-1-yl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-276:9-(3-aminoprop-1-yn-1-yl)-7-(2,6-difluorophenyl)-N-(3-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-277:4-({9-chloro-7-[2-(trifluoromethyl)phenyl]-5H-pyrimido[5,4-d][2]benzazepin-2-yl}amino)benzoic acid II-278:N-{4-[(3-aminoazetidin-1-yl)carbonyl]phenyl}-9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-279:4-[(9-chloro-7-pyridin-2-yl-5H-pyrimido[5,4-d][2]benzazepin-2-yl)amino]benzoic acid II-280:N-(4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}phenyl)-4-methylpiperazine-1-carboxamide II-281:9-chloro-N-(4-chloro-3-{[3-(methylamino)pyrrolidin-1-yl]carbonyl}phenyl)-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-282:9-chloro-N-(4-chloro-3-{[4-(methylamino)piperidin-1-yl]carbonyl}phenyl)-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-283:2-chloro-5-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-N-methyl-N-[2- (methylamino)ethyl]benzamideII-284:N-{4-[(3-aminopyrrolidin-1-yl)(imino)methyl]phenyl}-9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-285:2-(4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}phenyl)-1,4,5,6-tetrahydropyrimidin-5-ol II-286:N-{4-[(3-aminoazetidin-1-yl)carbonyl]phenyl}-9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-287:N-{4-[(4-aminopiperidin-1-yl)carbonyl]phenyl}-9-chloro-7-[2-(trifluoromethyl)phenyl]-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-288:9-chloro-N-(4-{[4-(methylamino)piperidin-1-yl]carbonyl}phenyl)-7-[2-(trifluoromethyl)phenyl]-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-289:N-{4-[(3-aminopyrrolidin-1-yl)carbonyl]phenyl}-9-chloro-7-[2-(trifluoromethyl)phenyl]-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-290:9-chloro-N-(4-{[3-(methylamino)pyrrolidin-1-yl]carbonyl}phenyl)-7-[2-(trifluoromethyl)phenyl]-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-291:9-chloro-N-(4-chloro-3-{[3-(methylamino)azetidin-1-yl]carbonyl}phenyl)-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-292:N-{3-[(4-aminopiperidin-1-yl)carbonyl]-4-chlorophenyl}-9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-293:9-chloro-7-(2,6-difluorophenyl)-N-(4-{[3-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-294:methyl 4-amino-1-(4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}benzoyl)piperidine-4-carboxylate II-295:4-amino-1-(4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}benzoyl)piperidine-4-carboxylic acid II-296:N-{4-[(3-aminoazetidin-1-yl)carbonyl]phenyl}-9-chloro-7-[2-(trifluoromethyl)phenyl]-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-297:9-chloro-N-(4-{[3-(methylamino)azetidin-1-yl]carbonyl}phenyl)-7-[2-(trifluoromethyl)phenyl]-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-298:N-{4-[(4-aminopiperidin-1-yl)carbonyl]phenyl}-9-chloro-7-pyridin-2-yl-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-299:N-{4-[(3-aminopyrrolidin-1-yl)carbonyl]phenyl}-9-chloro-7-pyridin-2-yl-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-300: ethyl2-amino-4-[(4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}benzoyl)amino]butanoate II-301:4-{[9-chloro-7-(3-fluoropyridin-2-yl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}benzoic acid II-302:9-{[3-(dimethylamino)azetidin-1-yl]carbonyl}-7-(2-fluorophenyl)-N-(3-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-303:7-(2-fluorophenyl)-2-[(3-methoxyphenyl)amino]-N-methyl-N-[3-(methylamino)propyl]-5H-pyrimido[5,4-d][2]benzazepine-9-carboxamideII-304: N-{(4-[(4-aminopiperidin-1-yl)carbonyl]phenyl}-9-chloro-7-(3-fluoropyridin-2-yl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-305:N-{4-[(3-aminopyrrolidin-1-yl)carbonyl]phenyl}-9-chloro-7-(3-fluoropyridin-2-yl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-306:2-(4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}phenyl)-4,5-dihydro-1H-imidazole-5-carboxylic acid II-307:N-(4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}phenyl)-2-(dimethylamino)acetamide II-308:2-amino-N-(4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}phenyl)-2-methylpropanamide II-309: ethyl(2R)-4-amino-2-[(4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}benzoyl)amino]butanoate II-310:4-(4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}benzoyl)-N-methylpiperazine-2-carboxamide II-311:7-(2-fluorophenyl)-2-[(3-methoxyphenyl)amino]-N-(3-morpholin-4-ylpropyl)-5H-pyrimido[5,4-d][2]benzazepine-9-carboxamide II-312:9-[(3,5-dimethylpiperazin-1-yl)carbonyl]-7-(2-fluorophenyl)-N-(3-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-313:9-chloro-N-(3-chloro-4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-314: ethyl2-(4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}phenyl)-4,5-dihydro-1H-imidazole-5-carboxylate II-315:9-chloro-N-(4-{[3-(methylamino)pyrrolidin-1-yl]carbonyl}phenyl)-7-pyridin-2-yl-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-316:9-chloro-N-(4-{[4-(methylamino)piperidin-1-yl]carbonyl}phenyl)-7-pyridin-2-yl-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-317:4-(4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}benzoyl)piperazine-2-carboxamide II-318:N-{4-[(3-aminopyrrolidin-1-yl)carbonyl]-3-chlorophenyl}-9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-319:N-(4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}phenyl)piperidine-4-carboxamide II-320:4-{[9-chloro-7-(2-fluoro-6-{methyl[2-(methylamino)ethyl]amino}phenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}benzoic acid II-321:9-chloro-7-(2,4-difluorophenyl)-N-{4-[(3,5-dimethylpiperazin-1-yl)carbonyl]phenyl}-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-322:9-chloro-7-(2,4-dimethoxyphenyl)-N-{4-[(3,5-dimethylpiperazin-1-yl)carbonyl]phenyl}-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-323:9-chloro-7-(2-chloro-6-fluorophenyl)-N-{4-[(3-methylpiperazin-1-yl)carbonyl]phenyl}-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-324:9-chloro-7-(2-chloro-6-fluorophenyl)-N-{4-[(3,5-dimethylpiperazin-1-yl)carbonyl]phenyl}-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-325:9-chloro-7-(2-chloro-6-fluorophenyl)-N-(4-{[4-(methylamino)piperidin-1-yl]carbonyl}phenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-326:9-chloro-7-(2-chloro-6-fluorophenyl)-N-(4-{[3-(methylamino)piperidin-1-yl]carbonyl}phenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-327:9-chloro-7-(2-chloro-6-fluorophenyl)-N-(4-{[3-(methylamino)pyrrolidin-1-yl]carbonyl}phenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-328:9-chloro-N-(3,4-dimethoxyphenyl)-7-{2-[(dimethylamino)methyl]phenyl}-5H-pyrimido[5,4-d][2]benzazepin-2- amineII-329: 9-chloro-7-(2-methoxyphenyl)-N-{4-[(3-methylpiperazin-1-yl)carbonyl]phenyl}-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-330:9-chloro-N-{4-[(3,5-dimethylpiperazin-1-yl)carbonyl]phenyl}-7-(2-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-331:9-chloro-7-(2-methoxyphenyl)-N-(4-{[4-(methylamino)piperidin-1-yl]carbonyl}phenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-332:9-chloro-7-(2-methoxyphenyl)-N-(4-{[3-(methylamino)pyrrolidin-1-yl]carbonyl}phenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-333:9-chloro-7-(2-methoxyphenyl)-N-(4-{[3-(methylamino)piperidin-1-yl]carbonyl}phenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-334:4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-N-methylbenzamide II-335:4-{[9-chloro-7-(2-fluoro-6-{methyl[3-(methylamino)propyl]amino}phenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}benzoic acid II-336: 4-{[9-chloro-7-(2-fluoro-6-{methyl[3-(methylamino)propyl]amino}phenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-N-methylbenzamide II-337:1-(4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}phenyl)ethanone II-338:N-[3-(3-aminoprop-1-yn-1-yl)phenyl]-9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-339:4-[(9-chloro-7-{2-fluoro-6-[(2-hydroxyethyl)amino]phenyl}-5H-pyrimido[5,4-d][2]benzazepin-2-yl)amino]-N-methylbenzamide II-340:4-[(7-{2-[(2-aminoethyl)amino]-6-fluorophenyl}-9-chloro-5H-pyrimido[5,4-d][2]benzazepin-2-yl)amino]-N-methylbenzamide II-341:4-amino-1-(4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}benzoyl)-N-methylpiperidine-4-carboxamideII-342:4-[(9-chloro-7-{2-[4-(dimethylamino)piperidin-1-yl]-6-fluorophenyl}-5H-pyrimido[5,4-d][2]benzazepin-2-yl)amino]-N-methylbenzamide II-343:9-chloro-7-(2,6-difluorophenyl)-N-{3-[3-(dimethylamino)prop-1-yn-1-yl]phenyl}-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-344:9-chloro-7-(2,6-difluorophenyl)-N-(3-iodophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-345:4-{[9-chloro-7-(2-{[2-(dimethylamino)ethyl]amino}-6-fluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-N-methylbenzamide II-346:4-[(9-chloro-7-{2-[[2-(dimethylamino)ethyl](methyl)amino]-6-fluorophenyl}-5H-pyrimido[5,4-d][2]benzazepin-2-yl)amino]-N-methylbenzamide II-347:4-{[9-chloro-7-(2-fluoro-6-{methyl[2-(methylamino)ethyl]amino}phenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-N-methylbenzamide II-348:4-({7-[2-(4-aminopiperidin-1-yl)-6-fluorophenyl]-9-chloro-5H-pyrimido[5,4-d][2]benzazepin-2-yl}amino)-N-methylbenzamide II-349:7-(2-fluorophenyl)-2-[(3-methoxyphenyl)amino]-N-methyl-N-[2-(methylamino)ethyl]-5H-pyrimido[5,4-d][2]benzazepine-9-carboxamideII-350: 4-amino-1-(4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}benzoyl)piperidine-4-carboxamide II-351:9-chloro-7-(2-chloro-6-fluorophenyl)-N-(4-{[3-(methylamino)azetidin-1-yl]carbonyl}phenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-352:9-chloro-7-(2,6-difluorophenyl)-N-(4-methyl-1,3-thiazol-2-yl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-353:7-(2,6-difluorophenyl)-2-[(3-methoxyphenyl)amino]-5H-pyrimido[5,4-d][2]benzazepine-9-carboxylic acid II-354:4-({9-chloro-7-[2-fluoro-6-(methylamino)phenyl]-5H-pyrimido[5,4-d][2]benzazepin-2-yl}amino)-N-methylbenzamide II-355:2-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-N-methyl-1,3-thiazole-4-carboxamide II-356:N-1H-benzimidazol-2-yl-9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-357:7-(2,6-difluorophenyl)-2-[(4-methyl-1,3-thiazol-2-yl)amino]-5H-pyrimido[5,4-d][2]benzazepine-9-carboxylic acid II-358:3-amino-1-(3-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}phenyl)propan-1-one II-359:1-(3-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}phenyl)-3-(dimethylamino)propan-1-one II-360:2-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-1,3-thiazole-4-carboxylic acid II-361: ethyl2-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-1,3-thiazole-4-carboxylate II-362:9-chloro-7-(2,6-difluorophenyl)-N-{4-[(3,5-dimethylpiperazin-1-yl)carbonyl]-1,3-thiazol-2-yl}-5H-pyrimido[5,4-d][2]benzazepin-2-amineII-363: ethyl 2-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-1,3-oxazole-5-carboxylate II-364:2-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-1,3-oxazole-5-carboxylic acid II-365:9-chloro-7-(2,6-difluorophenyl)-N-(4-{[(3R)-3-methylpiperazin-1-yl]carbonyl}-1,3-thiazol-2-yl)-5H-pyrimido[5,4-d][2]benzazepin-2-amineII-366: 9-chloro-7-(2,6-difluorophenyl)-N-(4-{[(2R)-2-methylpiperazin-1-yl]carbonyl}phenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-367:9-chloro-7-(2,6-difluorophenyl)-N-(4-{[3-(methylamino)pyrrolidin-1-yl]carbonyl}-1,3-thiazol-2-yl)-5H-pyrimido[5,4-d][2]benzazepin-2-amineII-368:2-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-1,3-oxazole-4-carboxylic acid II-369:9-chloro-7-(2,6-difluorophenyl)-N-{5-[(3,5-dimethylpiperazin-1-yl)carbonyl]-1,3-oxazol-2-yl}-5H-pyrimido[5,4-d][2]benzazepin-2-amineII-370:9-chloro-7-(2,6-difluorophenyl)-N-(5-{[3-(methylamino)pyrrolidin-1-yl]carbonyl}-1,3-oxazol-2-yl)-5H-pyrimido[5,4-d][2]benzazepin-2-amineII-371: 4-{[9-chloro-7-(2,6-difluorophenyl)-5-methyl-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}benzoic acid II-372:9-chloro-7-(2,6-difluorophenyl)-N-{3-[3-(dimethylamino)propyl]phenyl}-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-373:N-[3-(3-aminopropyl)phenyl]-9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-374:9-chloro-7-(2,6-difluorophenyl)-N-{4-[(3,5-dimethylpiperazin-1-yl)carbonyl]-1,3-oxazol-2-yl}-5H-pyrimido[5,4-d][2]benzazepin-2-amineII-375:9-chloro-7-(2,6-difluorophenyl)-N-(4-{[3-(methylamino)pyrrolidin-1-yl]carbony}-1,3-oxazol-2-yl)-5H-pyrimido[5,4-d][2]benzazepin-2-amineII-376: 7-(2,6-difluorophenyl)-2-({4-[(3,5-dimethylpiperazin-1-yl)carbonyl]phenyl}amino)-N-methyl-5H-pyrimido[5,4-d][2]benzazepine-9-carboxamide II-377:2-{[4-(aminocarbonyl)phenyl]amino}-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepine-9-carboxylic acid II-378:1-(4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4d][2]benzazepin-2-yl]amino}benzoyl)-N-methyl-4-(methylamino)piperidine-4-carboxamideII-379:N-{4-[(3-amino-3-methylpyrrolidin-1-yl)carbonyl]phenyl}-9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-380:9-chloro-7-(2,6-difluorophenyl)-N-(4-{[3-methyl-3-(methylamino)pyrrolidin-1-yl]carbonyl}phenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-381:1-(4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}benzoyl)-4-(methylamino)piperidine-4-carboxamide II-382:9-chloro-7-(2,6-difluorophenyl)-N-{4-[(3,3,5-trimethylpiperazin-1-yl)carbonyl]phenyl}-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-383:N-1-azabicyclo[2.2.2]oct-3-yl-4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-N-methylbenzamide II-384:N-1-azabicyclo[2.2.2]oct-3-yl-4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}benzamide II-385:4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-N-hydroxybenzamide II-386:N-{4-[(aminooxy)carbonyl]phenyl}-9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-387:4-{[9-chloro-7-(2,6-difluorophenyl)-7H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}benzoic acid II-388:4-{[9-chloro-7-(2,3-difluorophenyl)-7H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}benzoic acid II-389:3-amino-1-(4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}benzoyl)-N-methylpyrrolidine-3- carboxamideII-390:3-amino-1-(2-chloro-4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}benzoyl)pyrrolidine-3-carboxamide II-391:9-chloro-7-(2,6-difluorophenyl)-N-{4-[(3,3-dimethylpiperazin-1-yl)carbonyl]phenyl}-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-392:4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)benzamide II-393:9-chloro-7-(2,6-difluorophenyl)-N-(4-{[3-(dimethylamino)-3-methylpyrrolidin-1-yl]carbonyl}phenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-394:9-chloro-7-(2,6-difluorophenyl)-N-(3-methyl-1H-pyrazol-5-yl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-395:2-chloro-4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}benzoic acid II-396:4-amino-1-(2-chloro-4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}benzoyl)-N-methylpiperidine-4- carboxamideII-397:4-amino-1-(2-chloro-4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}benzoyl)-N,N-dimethylpiperidine-4-carboxamide II-398:4-[(9-methoxy-7-oxo-6,7-dihydro-5H-pyrimido[5,4-d][2]benzazepin-2-yl)amino]benzoic acid II-399:2-({4-[(3,5-dimethylpiperazin-1-yl)carbonyl]phenyl}amino)-9-methoxy-5,6-dihydro-7H-pyrimido[5,4-d][2]benzazepin-7-one II-400:9-methoxy-2-[(4-{[3-(methylamino)pyrrolidin-1-yl]carbonyl}phenyl)amino]-5,6-dihydro-7H-pyrimido[5,4-d][2]benzazepin-7-one II-401:4-[(8-methyl-7-oxo-5,6,7,8-tetrahydropyrimido[5,4-c]pyrrolo[3,2-e]azepin-2-yl)amino]benzoic acid II-402:2-({4-[(3,5-dimethylpiperazin-1-yl)carbonyl]phenyl}amino)-8-methyl-5,8-dihydropyrimido[5,4-c]pyrrolo[3,2-e]azepin-7(6H)-one II-403:2-[(3-methoxyphenyl)amino]-8-methyl-5,8-dihydropyrimido[5,4-c]pyrrolo[3,2-e]azepin-7(6H)-one II-404:9-chloro-2-[(3,4-dimethoxyphenyl)amino]-5,6-dihydro-7H-pyrimido[5,4-d][2]benzazepin-7-one II-405:4-{[4-amino-9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}benzoic acid II-406:9-chloro-N-(3-chloro-4-{[4-(methylamino)piperidin-1-yl]carbonyl}phenyl)-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-407:9-chloro-N-(3-chloro-4-{[4-(methylamino)piperidin-1-yl]carbonyl}phenyl)-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-408:4-{[9-chloro-7-(2-fluoro-6-hydroxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}benzoic acid II-409:9-chloro-N-[4-(1,7-diazaspiro[4.4]non-7-ylcarbonyl)phenyl]-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-410:9-chloro-7-(2,6-difluorophenyl)-N-(4-{[2-(methylamino)-7-azabicyclo[2.2.1]hept-7-yl]carbonyl}phenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-411:1-(4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}benzoyl)-N-methyl-3-(methylamino)pyrrolidine-3- carboxamideII-412:1-(4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}benzoyl)-3-(methylamino)pyrrolidine-3-carboxamide II-413:1-(2-chloro-4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}benzoyl)-N-methyl-3-(methylamino)piperidine-3-carboxamide II-414:9-chloro-7-(2,6-difluorophenyl)-N-(4-{[3-methyl-3-(methylamino)piperidin-1-yl]carbonyl}phenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-415:9-chloro-7-(2-fluoro-6-methoxyphenyl)-N-(4-{[3-methyl-3-(methylamino)piperidin-1-yl]carbonyl}phenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-416:{2-Chloro-4-[9-chloro-7-(2-fluoro-6-methoxy-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-phenyl}-(3-methyl-3-methylamino-piperidin-1-yl)-methanone II-417:9-chloro-7-(2,6-difluorophenyl)-N-(4-{[4-methyl-4-(methylamino)piperidin-1-yl]carbonyl}phenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-418:9-chloro-7-(2,6-difluorophenyl)-N-(4-{[4-(dimethylamino)-4-methylpiperidin-1-yl]carbonyl}phenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-419:N-{4-[(4-amino-4-methylpiperidin-1-yl)carbonyl]phenyl}-9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-420:9-chloro-N-(3-chloro-4-{[4-methyl-4-(methylamino)piperidin-1-yl]carbonyl}phenyl)-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-421:9-chloro-7-(2-fluoro-6-methoxyphenyl)-N-(4-{[4-methyl-4-(methylamino)piperidin-1-yl]carbonyl}phenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-422:2-Chloro-4-[9-chloro-7-(2-fluoro-6-methoxy-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-phenyl}-(4-methyl-4-methylamino-piperidin-1-yl)-methanone II-423:9-chloro-7-(2-fluoro-6-methoxyphenyl)-N-(3-fluoro-4-{[4-methyl-4-(methylamino)piperidin-1-yl]carbonyl}phenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-424:9-chloro-N-{3-chloro-4-[(3,3,5,5-tetramethylpiperazin-1-yl)carbonyl]phenyl}-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-425:N-1-azabicyclo[2.2.2]oct-3-yl-4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-fluoro-N-methylbenzamideII-426:N-1-azabicyclo[2.2.2]oct-3-yl-4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-N-methylbenzamide II-427:N-8-azabicyclo[3.2.1]oct-3-yl-4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-N-methylbenzamide II-428:9-chloro-7-(2,6-difluorophenyl)-N-(4-{[3-(methylamino)-8-azabicyclo[3.2.1]oct-8-yl]carbonyl}phenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-429:9-chloro-7-(2-fluoro-6-methoxyphenyl)-N-(4-{[3-(methylamino)-8-azabicyclo[3.2.1]oct-8-yl]carbonyl}phenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-430:4-{[7-(2,6-difluorophenyl)-9-methyl-5H-pyrimido[5,4-c]thieno[2,3-e]azepin-2-yl]amino}benzoic acid II-431:7-(2,6-difluorophenyl)-N-{4-[(3,3,5,5-tetramethylpiperazin-1-yl)carbonyl]phenyl}-5H-pyrimido[5,4-c]thieno[2,3-e]azepin-2-amineII-432: N-{4-[(3-amino-3-methylpyrrolidin-1-yl)carbonyl]phenyl}-7-(2,6-difluorophenyl)-10-methyl-5,10-dihydropyrimido[5,4-c]pyrrolo[2,3-e]azepin-2-amine II-433:7-(2,6-difluorophenyl)-9-methyl-N-(4-{[3-(methylamino)pyrrolidin-1-yl]carbonyl}phenyl)-5H-furo[2,3-c]pyrimido[4,5-e]azepin-2-amine II-434:4-(2,6-difluorophenyl)-2-methyl-N-(4-{[3-methyl-3-(methylamino)pyrrolidin-1-yl]carbonyl}phenyl)-6H-pyrimido[5,4-c][1,3]thiazolo[4,5-e]azepin-9-amine II-435:N-{4-[(3-amino-3-methylpyrrolidin-1-yl)carbonyl]phenyl}-7-(2-fluoro-6-methoxyphenyl)-5,9-dihydropyrimido[5,4-c]pyrrolo[3,4-e]azepin-2-amineII-436: 4-{[4-(2,6-difluorophenyl)-1-methyl-1,6-dihydropyrazolo[4,3-c]pyrimido[4,5-e]azepin-9-yl]amino}benzoic acid II-437:1-{4-[4-(2,6-Difluoro-phenyl)-2-methyl-6H-3-thia-5,8,10-triaza-benzo[e]azulen-9-ylamino]-benzoyl}-4-dimethylamino-piperidine-4-carboxylic acid methylamide II-438:4-(4-{[7-(2,6-difluorophenyl)-5H-furo[3,2-c]pyrimido[4,5-e]azepin-2-yl]amino}benzoyl)-N-methylpiperazine-2-carboxamide II-439:4-(4-{[4-(2,6-difluorophenyl)-6H-isoxazolo[4,5-c]pyrimido[4,5-e]azepin-9-yl]amino}benzoyl)-N-methylpiperazine-2-carboxamide II-440:4-(2,6-difluorophenyl)-9-[(4-{[3-methyl-3-(methylamino)pyrrolidin-1-yl]carbonyl}phenyl)amino]-3,6-dihydroimidazo[4,5-c]pyrimido[4,5-e]azepin-2(1H)-one II-441:2-amino-N-(3-{[7-(2,6-difluorophenyl)-8,10-dimethyl-5H-pyrimido[5,4-c]thieno[3,4-e]azepin-2-yl]amino}phenyl)-N,2-dimethylpropanamide II-442:9-chloro-7-(2,6-difluorophenyl)-N-{3-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]phenyl}-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-443:4-(4-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}phenyl)-N-methyl-1-(methylamino)cyclohexanecarboxamideII-444: 7-(3-{[7-(2-fluoro-6-methoxyphenyl)-9-methoxy-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}phenyl)-1,7-diazaspiro[4.4]nonan-6-oneII-445:9-chloro-N-[4-(3,8-diazabicyclo[3.2.1]oct-3-ylcarbonyl)phenyl]-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-446:1-(3-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}phenyl)-3,5,5-trimethylpiperazin-2-one II-447:9-chloro-N-[4-(2,6-dimethylpiperidin-4-yl)phenyl]-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-448:N-[4-(1-amino-1-methylethyl)phenyl]-9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-449:N-[4-(2,5-diazaspiro[3.4]oct-2-ylcarbonyl)phenyl]-7-(2,6-difluorophenyl)-10-methyl-5H-isothiazolo[5,4-c]pyrimido[4,5-e]azepin-2-amine II-450:4-(2,6-difluorophenyl)-1-methyl-9-[(4-{[4-methyl-4-(methylamino)piperidin-1-yl]carbonyl}phenyl)amino]-1,6-dihydro-2H-pyrimido[5,4-c][1,3]thiazolo[4,5-e]azepin-2-one II-451:4-(2,6-difluorophenyl)-N-[4-(1H-imidazol-2-yl)phenyl]-1-methyl-1,6-dihydroimidazo[4,5-c]pyrimido[4,5-e]azepin-9-amine II-452:4-{[7-(2,6-difluorophenyl)-5H-[1]benzofuro[2,3-c]pyrimido[4,5-e]azepin-2-yl]amino}benzoic acid II-453:7-(2-fluorophenyl)-N-{4-[(3,3,5,5-tetramethylpiperazin-1-yl)carbonyl]phenyl}-8,9,10,11-tetrahydro-5H-pyrido[4′,3′:4,5]thieno[3,2-c]pyrimido[4,5-e]azepin-2-amine II-454:9-bromo-7-(2-fluorophenyl)-N-(4-{[3-(methylamino)pyrrolidin-1-yl]carbonyl}phenyl)-5,8-dihydropyrimido[5,4-c]pyrrolo[3,2-e]azepin-2-amine II-455: 7-(2-fluorophenyl)-N-(3-methyl-1H-indazol-6-yl)-5,12-dihydropyrimido[4′,5′:5,6]azepino[4,3-b]indol-2-amine II-456:1-(4-{[7-(2,6-difluorophenyl)-9,10-dimethyl-5,8-dihydropyrimido[5,4-c]pyrrolo[3,2-e]azepin-2-yl]amino}benzoyl)-3-(methylamino)pyrrolidine-3-carboxamide II-457:{3-[9-Chloro-7-(2-fluoro-6-methoxy-phenyl)-5H-benzo[c]pyrimido-[4,5-e]azepin-2-ylamino]-phenyl}-(4-methyl-piperazin-1-yl)-methanoneII-458:[9-Chloro-7-(2,6-difluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl]-(2-methylaminomethyl-benzothiazol-6-yl)-amine II-459:4-[9-Chloro-7-(2-isopropoxy-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-benzoic acid II-460:4-[9-Chloro-7-(2-fluoro-6-isopropoxy-phenyl)-5H-benzo[c]pyrimido-[4,5-e]azepin-2-ylamino]-benzoic acid II-461:4-[9-Chloro-7-(2-ethoxy-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-benzoic acid II-462:4-[9-Chloro-7-(2-ethoxy-6-fluoro-phenyl)-5H-benzo[c]pyrimido-[4,5-e]azepin-2-ylamino]-benzoic acid II-463:4-[9-Chloro-7-(2-fluoro-6-methyl-phenyl)-5H-benzo[c]pyrimido-[4,5-e]azepin-2-ylamino]-benzoic acid II-464:4-[9-Chloro-7-(2-trifluoromethoxy-phenyl)-5H-benzo[c]pyrimido-[4,5-e]azepin-2-ylamino]-benzoic acid II-465:4-[9-Chloro-7-(2-fluoro-6-trifluoromethoxy-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-benzoic acid II-466:4-[9-Chloro-7-(3-fluoro-2-trifluoromethoxy-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-benzoic acid II-467:4-[9-Chloro-7-(2,3-dimethoxy-phenyl)-5H-benzo[c]pyrimido-[4,5-e]azepin-2-ylamino]-benzoic acid II-468:4-[9-Chloro-7-(2-isobutyl-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-benzoic acid II-469:4-(7-Benzofuran-2-yl-9-chloro-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino)-benzoic acid II-470:4-[9-Chloro-7-(1-methyl-1H-pyrrol-2-yl)-5H-benzo[c]pyrimido-[4,5-e]azepin-2-ylamino]-benzoic acid II-471:4-[9-Chloro-7-(1-methyl-1H-imidazol-2-yl)-5H-benzo[c]pyrimido-[4,5-e]azepin-2-ylamino]-benzoic acid II-472:4-(9-Chloro-7-thiophen-2-yl-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino)-benzoic acid II-473:4-[9-Chloro-7-(2H-pyrazol-3-yl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-benzoic acid II-474:4-[9-Chloro-7-(2-ethynyl-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-benzoic acid II-475:4-[7-(2-Aminomethyl-phenyl)-9-chloro-5H-benzo[c]pyrimido-[4,5-e]azepin-2-ylamino]-benzoic acid II-476:4-[9-Chloro-7-(5-fluoro-2-methoxy-phenyl)-5H-benzo[c]pyrimido-[4,5-e]azepin-2-ylamino]-benzoic acid II-477:4-[9-Chloro-7-(3-methoxy-pyridin-2-yl)-5H-benzo[c]pyrimido-[4,5-e]azepin-2-ylamino]-benzoic acid II-478:4-[8-Fluoro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-benzoic acid II-479:4-[8-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-benzoic acid II-480:4-[11-Fluoro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-benzoic acid II-481:4-[11-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-benzoic acid II-482:6-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-pyridazine-3-carboxylic acid II-483:2-[9-Chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-1H-imidazole-4-carboxylic acid II-484:4-[9-Chloro-7-(2-fluoro-phenyl)-4-methyl-5H-benzo[c]pyrimido-[4,5-e]azepin-2-ylamino]-benzoic acid II-485:4-[4-Aminomethyl-9-chloro-7-(2-fluoro-phenyl)-5H-benzo[c]pyrimido-[4,5-e]azepin-2-ylamino]-benzoic acid II-486:4-(9-Aminomethyl-7-phenyl-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino)-benzoic acid II-487:9-Chloro-7-(2-fluorophenyl)-N-{4-[(2-methylpiperazin-1-yl)carbonyl]phenyl}-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-488:4-{[9-Chloro-7-(2-fluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-N-[{3-[(dimethylamino)methyl]azetidin-1-yl}(imino)methyl]benzamide II-489:4-{[9-Chloro-7-(2-fluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-N-[imino(piperazin-1-yl)methyl]benzamide II-490:4-{[9-Chloro-7-(2-fluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-N-[imino(3-methylpiperazin-1-yl)methyl]benzamide II-491:4-{[9-Chloro-7-(2-fluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-N-[[3-(dimethylamino)pyrrolidin-1- yl](imino)methyl]benzamideII-492:4-{[9-Chloro-7-(2-fluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-N-[imino(4-methylpiperazin-1-yl)methyl]benzamide II-493:4-{[9-Chloro-7-(2-fluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-N-[(3,5-dimethylpiperazin-1-yl)(imino)methyl]benzamide II-494:1-[[(4-{[9-Chloro-7-(2-fluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}benzoyl)amino](imino)methyl]pyrrolidine-3-carboxamide II-495:1-[[(4-{[9-Chloro-7-(2-fluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}benzoyl)amino](imino)methyl]piperidine-3-carboxamide II-496:4-{[9-Chloro-7-(2-fluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-N-[{4-[(cyclopropylcarbonyl)amino]piperidin-1-yl}(imino)methyl]benzamide II-497:4-{[9-Chloro-7-(2-fluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-N-[(dimethylamino)(imino)methyl]benzamide II-498:N-[[(4-{[9-Chloro-7-(2-fluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}phenyl)amino](imino)methyl]cyclopropanecarboxamide II-499:N-[[(4-{[9-Chloro-7-(2-fluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}phenyl)amino](imino)methyl]-3-(dimethylamino)cyclopentanecarboxamide II-500:4-({9-Chloro-7-[2-fluoro-6-(trifluoromethyl)phenyl]-5H-pyrimido-[5,4-d][2]benzazepin-2-yl}amino)benzoic acid II-501:4-{[9-Chloro-7-(2,6-dichlorophenyl)-5H>-pyrimido[5,4-d][2]benzazepin-2-yl]amino}benzoic acid II-502:4-{[9-Chloro-7-(2-fluoro-6-methylphenyl)-5H-pyrimido-[5,4-d][2]benzazepin-2-yl]amino}benzoic acid II-503:4-{[7-(2-Bromo-6-chlorophenyl)-9-chloro-5H-pyrimido-[5,4-d][2]benzazepin-2-yl]amino}benzoic acid II-504:9-Chloro-7-(2,6-difluorophenyl)-N-{4-[(3,5-dimethylpiperazin-1-yl)carbonyl]-3-fluorophenyl}-5H-pyrimido[5,4-d][2]benzazepin-2-amineII-505:4-{[9-Chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-N-[(3,5-dimethylpiperazin-1-yl)(imino)methyl]-N-methylbenzamide II-506:4-{[9-Chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-N-[[3-(dimethylamino)azetidin-1-yl](imino)methyl]-N-methylbenzamide II-507:3-{[9-Chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-N-[(3,5-dimethylpiperazin-1-yl)(imino)methyl]benzamide II-508:3-{[9-Chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-N-[[3-(dimethylamino)pyrrolidin-1- yl](imino)methyl]benzamideII-509: 9-Chloro-7-(2,6-difluorophenyl)-N-{3-[(3,5-dimethylpiperazin-1-yl)carbonyl]-4-fluorophenyl}-5H-pyrimido[5,4-d][2]benzazepin-2-amineII-510: N-[[(4-{[9-Chloro-7-(2,6-difluorophenyl)-5H-pyrimido-[5,4-d][2]benzazepin-2-yl]amino}phenyl)amino](imino)methyl]-3-(dimethylamino)cyclopentanecarboxamide II-511:N-[[(4-{[9-Chloro-7-(2,6-difluorophenyl)-5H-pyrimido-[5,4-d][2]benzazepin-2-yl]amino}-2-fluorophenyl)amino](imino)methyl]-3-(dimethylamino)cyclopentanecarboxamide II-512:N-[[(5-{[9-Chloro-7-(2,6-difluorophenyl)-5H-pyrimido-[5,4-d][2]benzazepin-2-yl]amino)}-2-fluorophenyl)amino](imino)methyl]-3-(dimethylamino)cyclopentanecarboxamide II-513:N-(4-{[9-Chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}phenyl)-3,5-dimethylpiperazine-1-carboximidamide II-514:4-{[9-Chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-N-[[3-(dimethylamino)pyrrolidin-1-yl](imino)methyl]-N-methylbenzamide II-515:N-(3-{[9-Chloro-7-(2,6-difluorophenyl)-5<i>H</i>-pyrimido-[5,4-d][2]benzazepin-2-yl]amino}phenyl)-3,5-dimethylpiperazine-1-carboximidamide II-516:N-(3-{[9-Chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}phenyl)-N,3,5-trimethylpiperazine-1-carboximidamide II-517:3-{[9-Chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-N-[[3-(dimethylamino)azetidin-1-yl](imino)methyl]benzamideII-518:N-(5-{[9-Chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-fluorophenyl)-N,3,5-trimethylpiperazine-1- carboximidamideII-519: N-[[(3-{[9-Chloro-7-(2,6-difluorophenyl)-5H-pyrimido-[5,4-d][2]benzazepin-2-yl]amino}phenyl)amino](imino)methyl]-3-(dimethylamino)cyclopentanecarboxamide II-520:9-Chloro-7-(2,6-difluorophenyl)-N-{3-[(3,5-dimethylpiperazin-1-yl)(imino)methyl]phenyl}-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-521:N-(4-{[9-Chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}phenyl)-N,3,5-trimethylpiperazine-1-carboximidamide II-522:N-(4-{[9-Chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-fluorophenyl)-3,5-dimethylpiperazine-1-carboximidamideII-523: 9-Chloro-7-(2,6-difluorophenyl)-N-{4-[(3,5-dimethylpiperazin-1-yl)(imino)methyl]-3-fluorophenyl}-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-524:5-{[9-Chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-(2,6-dimethylpiperidin-4-yl)-1H-isoindole-1,3(2H)-dioneII-525:N-[2-(Aminomethyl)-1H-benzimidazol-6-yl]-9-chloro-7-(2-fluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-526:9-Chloro-7-(2-fluorophenyl)-N-{2-[(methylamino)methyl]-1H-benzimidazol-6-yl}-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-527:9-Chloro-N-{2-[(dimethylamino)methyl]-1H-benzimidazol-6-yl}-7-(2-fluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-528:9-Chloro-7-(2-fluorophenyl)-N-{2-[(methylamino)methyl]-1,3-benzothiazol-6-yl}-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-529:9-Chloro-7-(2,6-difluorophenyl)-N-{2-[(methylamino)methyl]-1H-benzimidazol-6-yl}-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-530:9-Chloro-7-(2,6-difluorophenyl)-N-{2-[(methylamino)methyl]-1,3-benzoxazol-6-yl}-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-531:9-Chloro-7-(2-fluorophenyl)-N-{2-[(methylamino)methyl]-1,3-benzoxazol-6-yl}-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-532:9-Chloro-7-(2,6-difluorophenyl)-N-{3-[(3,5-dimethylpiperazin-1-yl)(imino)methyl]-4-fluorophenyl}-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-533:9-Chloro-7-(2,6-difluorophenyl)-N-{2-[(methylamino)methyl]-1,3-benzothiazol-6-yl}-5H-pyrimido[5,4-d][2]benzazepin-2-amine II-534:{3-[9-Chloro-7-(2,6-difluorophenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-phenyl}-(4-methyl-piperazin-1-yl)-methanone II-535:3-[9-Chloro-7-(2,6-difluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-ylamino]-N-methyl-N-(4-methyl-pentyl)-benzamide

In some embodiments, the Aurora kinase inhibitor is represented byformula (III):

or a pharmaceutically acceptable salt thereof;

wherein:

-   -   R^(a) is selected from the group consisting of C₁₋₃ aliphatic,        C₁₋₃ fluoroaliphatic, -T-R¹, —R², and -T-R²;        -   T is a C₁₋₃ alkylene chain optionally substituted with            fluoro;        -   R¹ is an optionally substituted aryl, heteroaryl, or            heterocyclyl group;        -   R² is selected from the group consisting of halo, —C≡C—R³,            —CH═CH—R³, —N(R⁴)₂, and —OR⁵;        -   R³ is hydrogen or an optionally substituted aliphatic, aryl,            heteroaryl, or heterocyclyl group;        -   each R⁴ independently is hydrogen or an optionally            substituted aliphatic, aryl, heteroaryl, or heterocyclyl            group; or two R⁴ on the same nitrogen atom, taken together            with the nitrogen atom form an optionally substituted 5- to            6-membered heteroaryl or 4- to 8-membered heterocyclyl ring            having, in addition to the nitrogen atom, 0-2 ring            heteroatoms selected from N, O, and S;        -   R⁵ is hydrogen or an optionally substituted aliphatic, aryl,            heteroaryl, or heterocyclyl group; and    -   R^(b) is selected from the group consisting of fluoro, chloro,        —CH₃, —CF₃, —OH, —OCH₃, —OCF₃, —OCH₂CH₃, and —OCH₂CF₃.

In some embodiments, R¹ is a 5- or 6-membered aryl, heteroaryl, orheterocyclyl ring optionally substituted with one or two substituentsindependently selected from the group consisting of halo, C₁₋₃aliphatic, and C₁₋₃ fluoroaliphatic. In certain embodiments, R¹ is aphenyl, furyl, pyrrolidinyl, or thienyl ring optionally substituted withone or two substituents independently selected from the group consistingof halo, C₁₋₃ aliphatic, and C₁₋₃ fluoroaliphatic.

In some embodiments, R³ is hydrogen, C₁₋₃ aliphatic, C₁₋₃fluoroaliphatic, or —CH₂—OCH₃.

In some embodiments, R⁵ is hydrogen, C₁₋₃ aliphatic, or C₁₋₃fluoroaliphatic.

In certain embodiments, R^(a) is halo, C₁₋₃ aliphatic, C₁₋₃fluoroaliphatic, —OH, —O(C₁₋₃ aliphatic), —O(C₁₋₃ fluoroaliphatic),—C═C—R³, —CH═CH—R³, or an optionally substituted pyrrolidinyl, thienyl,furyl, or phenyl ring, wherein R³ is hydrogen, C₁₋₃ aliphatic, C₁₋₃fluoroaliphatic, or —CH₂—OCH₃. In certain particular embodiments, R^(a)is selected from the group consisting of chloro, fluoro, C₁₋₃ aliphatic,C₁₋₃ fluoroaliphatic, —OCH₃, —OCF₃, —C≡C—CH₃, —C≡C—CH₂OCH₃, —CH═CH₂,—CH═CHCH₃, N-methylpyrrolidinyl, thienyl, methylthienyl, furyl,methylfuryl, phenyl, fluorophenyl, and tolyl.

Table 2 provides the chemical names for specific examples of compoundsof formula (III).

TABLE 2 Examples of Compounds of Formula (III) Chemical Name III-14-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoic acid III-24-{[9-ethynyl-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoic acid III-34-({9-chloro-7-[2-fluoro-6-(trifluoromethoxy)phenyl]-5H-pyrimido[5,4-d][2]benzazepin-2-yl}amino)-2-methoxybenzoic acid III-44-{[7-(2-fluoro-6-methoxyphenyl)-9-(1-methyl-1H-pyrrol-2-yl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoic acid III-54-{[7-(2-fluoro-6-methoxyphenyl)-9-(4-methyl-3-thienyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoic acid III-64-{[7-(2-fluoro-6-methoxyphenyl)-9-(3-methyl-2-furyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoic acid III-74-({9-ethynyl-7-[2-fluoro-6-(2,2,2-trifluoroethoxy)phenyl]-5H-pyrimido[5,4-d][2]benzazepin-2-yl}amino)-2-methoxybenzoic acid III-84-{[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoic acid III-94-{[7-(2-fluoro-6-methoxyphenyl)-9-(2-methylphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoic acid III-104-{[7-(2-fluoro-6-methoxyphenyl)-9-prop-1-yn-1-yl-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoic acid III-114-{[7-(2-fluoro-6-methoxyphenyl)-9-vinyl-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoic acid III-124-{[7-(2-fluoro-6-methoxyphenyl)-9-(2-fluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoic acid III-134-{[7-(2-fluoro-6-methoxyphenyl)-9-(3-methoxyprop-1-yn-1-yl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoic acid III-144-({7-(2-fluoro-6-methoxyphenyl)-9-[(1E)-prop-1-en-1-yl]-5H-pyrimido[5,4-d][2]benzazepin-2-yl}amino)-2-methoxybenzoic acid III-154-({9-chloro-7-[2-fluoro-6-(2,2,2-trifluoroethoxy)phenyl]-5H-pyrimido[5,4-d][2]benzazepin-2-yl}amino)-2-methoxybenzoic acid III-164-{[7-(2-fluoro-6-methoxyphenyl)-9-(2-furyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoic acid III-174-{[9-chloro-7-(2-fluoro-6-hydroxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoic acid III-184-{[7-(2-fluoro-6-methoxyphenyl)-9-phenyl-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoic acid

In one embodiment, the compound of formula (III) is4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoicacid or a pharmaceutically acceptable salt thereof. In a particularembodiment, the compound of formula (III) is sodium4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoate.

Any antibody capable of binding the CD20 antigen may be used in themethods of the instant invention. Antibodies which bind the CD20 antigeninclude, for example: C2138 (rituximab; RITUXAN®) (U.S. Pat. No.5,736,137, expressly incorporated herein by reference); theyttrium-[90]-labeled 2138 murine antibody designated Y2B8 (U.S. Pat. No.5,736,137, expressly incorporated herein by reference); murine IgG2a 131optionally labeled with 131 1 to generate the 131 1-B1 antibody(BEXXAR®) (U.S. Pat. No. 5,595,721, expressly incorporated herein byreference); murine monoclonal antibody 1F5 (Press et al. Blood 69(2):584-591 (1987)); chimeric 2H7 antibody (U.S. Pat. No. 5,677,180expressly incorporated herein by reference); and monoclonal antibodiesL27, G28-2, 93-1 133, B—Cl or NU-B2 available from the InternationalLeukocyte Typing Workshop (Valentine et al., In: Leukocyte Typing III(McMichael, Ed., p. 440, Oxford University Press (1987)).

In some embodiments, the anti-CD20 antibody is rituximab. Rituximab is agenetically engineered chimeric murine/human monoclonal antibody.Rituximab is an IgG, kappa immunoglobulin containing murine light andheavy chain variable region sequences and human constant regionsequences. Rituximab has a binding affinity for the CD20 antigen ofapproximately 8.0 nM. It is commercially available, e.g., from Genentech(South San Francisco, Calif.).

In some embodiments, the anti-CD20 antibody used in the presentinvention may be administered along with standard of carechemotherapeutic agents/combinations, such as, for example, CHOPchemotherapy regimen, which is a regimen consisting of the combinationof cyclophosphamide, doxorubicin, vincristine and prednisolone.Rituximab has been approved in combination with CHOP chemotherapy forthe treatment of certain types of lymphomas and this combination hasbecome known as RCHOP chemotherapy.

Compounds of formulas (I), (II) and (III), as well as compoundsdisclosed in, for example, WO 05/111039, US2005/0256102, US2007/0185087,WO 08/021,038, US2008/0045501, WO 08/063,525, US2008/0167292, WO07/113,212, EP1644376, US2005/0032839, WO 05/005427, WO 06/070192, WO06/070198, WO 06/070202, WO 06/070195, WO 06/003440, WO 05/002576, WO05/002552, WO 04/071507, WO 04/058781, WO 06/055528, WO 06/055561, WO05/118544, WO 05/013996, WO 06/036266, US2006/0160874, US2007/0142368,WO 04/043953, WO 07/132,220, WO 07/132,221, WO 07/132,228, WO 04/00833and WO 07/056,164 are inhibitors of Aurora kinase. The compounds can beassayed in vitro or in vivo for their ability to bind to and/or inhibitan Aurora kinase. In vitro assays include assays to determine inhibitionof the ability of an Aurora kinase to phosphorylate a substrate proteinor peptide. Alternate in vitro assays quantitate the ability of thecompound to bind to an Aurora kinase. Inhibitor binding may be measuredby radiolabelling the inhibitor prior to binding, isolating theinhibitor/Aurora kinase complex and determining the amount of radiolabelbound. Alternatively, inhibitor binding may be determined by running acompetition experiment in which new inhibitors are incubated with Aurorakinase bound to a known radioligand. The compounds also can be assayedfor their ability to affect cellular or physiological functions mediatedby Aurora kinase activity. Assays for each of these activities are knownin the art.

In another aspect, therefore, the invention provides a method forinhibiting cellular growth/cellular proliferation comprising contactinga cell with an Aurora kinase inhibitor in combination with an anti-CD20antibody, such as, e.g., rituximab. In an another embodiement, theinvention provides a method for inhibiting cellular growth/cellularproliferation comprising contacting a cell with an Aurora kinaseinhibitor in combination RCHOP chemotherapy.

Preferably, the method according to the invention causes an inhibitionof cell proliferation of the contacted cells. The phrase “inhibitingcell proliferation” is used to denote an ability of an inhibitor ofAurora kinase and/or anti-CD20 antibody to inhibit cell number or cellgrowth in contacted cells as compared to cells not contacted with theinhibitor and/or antibody. An assessment of cell proliferation can bemade by counting cells using a cell counter or by an assay of cellviability, e.g., a BrdU, MTT, XIT, or WST assay. Where the cells are ina solid growth (e.g., a solid tumor or organ), such an assessment ofcell proliferation can be made by measuring the growth, e.g., withcalipers, and comparing the size of the growth of contacted cells withnon-contacted cells.

Preferably, the growth of cells contacted with an Aurora kinaseinhibitor and an anti-CD20 antibody is retarded by at least about 50% ascompared to growth of non-contacted cells. In various embodiments, cellproliferation of contacted cells is inhibited by at least about 75%, atleast about 90%, or at least about 95% as compared to non-contactedcells. In some embodiments, the phrase “inhibiting cell proliferation”includes a reduction in the number of contacted cells, as compare tonon-contacted cells. Thus, an inhibitor of Aurora kinase and/or ananti-CD20 antibody that inhibits cell proliferation in a contacted cellmay induce the contacted cell to undergo growth retardation, to undergogrowth arrest, to undergo programmed cell death (i.e., apoptosis), or toundergo necrotic cell death.

In another aspect, the invention provides a pharmaceutical compositioncomprising i) an Aurora kinase inhibitor; and ii) an anti-CD20 antibody.In some embodiments the Aurora kinase inhibitor is selected from thegroup consisting of i) the compounds of formulas (I), (II) and (III);ii) the compounds disclosed in, for example, WO 05/111039,US2005/0256102, US2007/0185087, WO 08/021,038, US2008/0045501, WO08/063,525, US2008/0167292, WO 07/113,212, EP1644376, US2005/0032839, WO05/005427, WO 06/070192, WO 06/070198, WO 06/070202, WO 06/070195, WO06/003440, WO 05/002576, WO 05/002552, WO 04/071507, WO 04/058781, WO06/055528, WO 06/055561, WO 05/118544, WO 05/013996, WO 06/036266,US2006/0160874, US2007/0142368, WO 04/043953, WO 07/132,220, WO07/132,221, WO 07/132,228, WO 04/00833 and WO 07/056,164; andpharmaceutically acceptable salts thereof.

If a pharmaceutically acceptable salt of the Aurora kinase inhibitor isutilized in these compositions, the salt preferably is derived from aninorganic or organic acid or base. For reviews of suitable salts, see,e.g., Berge et al, J. Pharm. Sci. 66:1-19 (1977) and Remington: TheScience and Practice of Pharmacy, 20th Ed., ed. A. Gennaro, LippincottWilliams & Wilkins, 2000.

Nonlimiting examples of suitable acid addition salts include thefollowing: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphor sulfonate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,fumarate, lucoheptanoate, glycerophosphate, hemisulfate, heptanoate,hexanoate, hydrochloride, hydrobromide, hydroiodide,2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate,2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate,persulfate, 3-phenyl-propionate, picrate, pivalate, propionate,succinate, tartrate, thiocyanate, tosylate and undecanoate.

Suitable base addition salts include, without limitation, ammoniumsalts, alkali metal salts, such as sodium and potassium salts, alkalineearth metal salts, such as calcium and magnesium salts, salts withorganic bases, such as dicyclohexylamine, N-methyl-D-glucamine,t-butylamine, ethylene diamine, ethanolamine, and choline, and saltswith amino acids such as arginine, lysine, and so forth.

Also, basic nitrogen-containing groups may be quaternized with suchagents as lower alkyl halides, such as methyl, ethyl, propyl, and butylchlorides, bromides and iodides; dialkyl sulfates, such as dimethyl,diethyl, dibutyl and diamyl sulfates, long chain halides such as decyl,lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkylhalides, such as benzyl and phenethyl bromides and others. Water oroil-soluble or dispersible products are thereby obtained.

The term “pharmaceutically acceptable carrier” is used herein to referto a material that is compatible with a recipient subject, preferably amammal, more preferably a human, and is suitable for delivering anactive agent to the target site without terminating the activity of theagent. The toxicity or adverse effects, if any, associated with thecarrier preferably are commensurate with a reasonable risk/benefit ratiofor the intended use of the active agent.

The terms “carrier”, “adjuvant”, or “vehicle” are used interchangeablyherein, and include any and all solvents, diluents, and other liquidvehicles, dispersion or suspension aids, surface active agents, isotonicagents, thickening or emulsifying agents, preservatives, solid binders,lubricants and the like, as suited to the particular dosage formdesired. Remington: The Science and Practice of Pharmacy, 20th Ed., ed.A. Gennaro, Lippincott Williams & Wilkins, 2000 discloses variouscarriers used in formulating pharmaceutically acceptable compositionsand known techniques for the preparation thereof. Except insofar as anyconventional carrier medium is incompatible with the compounds of theinvention, such as by producing any undesirable biological effect orotherwise interacting in a deleterious manner with any othercomponent(s) of the pharmaceutically acceptable composition, its use iscontemplated to be within the scope of this invention. Some examples ofmaterials which can serve as pharmaceutically acceptable carriersinclude, but are not limited to, ion exchangers, alumina, aluminumstearate, lecithin, serum proteins, such as human serum albumin, buffersubstances such as disodium hydrogen phosphate, potassium hydrogenphosphate, sodium carbonate, sodium bicarbonate, potassium carbonate,potassium bicarbonate, magnesium hydroxide and aluminum hydroxide,glycine, sorbic acid, or potassium sorbate, partial glyceride mixturesof saturated vegetable fatty acids, water, pyrogen-free water, salts orelectrolytes such as protamine sulfate, disodium hydrogen phosphate,potassium hydrogen phosphate, sodium chloride, and zinc salts, colloidalsilica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates,waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugarssuch as lactose, glucose, sucrose, starches such as corn starch andpotato starch, cellulose and its derivatives such as sodiumcarboxymethyl cellulose, ethyl cellulose and cellulose acetate, powderedtragacanth; malt, gelatin, talc, excipients such as cocoa butter andsuppository waxes, oils such as peanut oil, cottonseed oil, saffloweroil, sesame oil, olive oil, corn oil and soybean oil, glycols such aspropylene glycol and polyethylene glycol, esters such as ethyl oleateand ethyl laurate, agar, alginic acid, isotonic saline, Ringer'ssolution, alcohols such as ethanol, isopropyl alcohol, hexadecylalcohol, and glycerol, cyclodextrins, lubricants such as sodium laurylsulfate and magnesium stearate, petroleum hydrocarbons such as mineraloil and petrolatum. Coloring agents, releasing agents, coating agents,sweetening, flavoring and perfuming agents, preservatives andantioxidants can also be present in the composition, according to thejudgment of the formulator.

The pharmaceutical compositions of the invention can be manufactured bymethods well known in the art such as conventional granulating, mixing,dissolving, encapsulating, lyophilizing, or emulsifying processes, amongothers. Compositions may be produced in various forms, includinggranules, precipitates, or particulates, powders, including freezedried, rotary dried or spray dried powders, amorphous powders, tablets,capsules, syrup, suppositories, injections, emulsions, elixirs,suspensions or solutions. Formulations may optionally contain solvents,diluents, and other liquid vehicles, dispersion or suspension aids,surface active agents, pH modifiers, isotonic agents, thickening oremulsifying agents, stabilizers and preservatives, solid binders,lubricants and the like, as suited to the particular dosage formdesired.

According to a preferred embodiment, the compositions of this inventionare formulated for pharmaceutical administration to a mammal, preferablya human being. Such pharmaceutical compositions of the present inventionmay be administered orally, parenterally, by inhalation spray,topically, rectally, nasally, buccally, vaginally or via an implantedreservoir. The term “parenteral” as used herein includes subcutaneous,intravenous, intramuscular, intra-articular, intra-synovial,intrasternal, intrathecal, intrahepatic, intralesional and intracranialinjection or infusion techniques. Preferably, the compositions areadministered orally, intravenously, or subcutaneously. The formulationsof the invention may be designed to be short-acting, fast-releasing, orlong-acting. Still further, compounds can be administered in a localrather than systemic means, such as administration (e.g., by injection)at a tumor site.

Liquid dosage forms for oral administration include, but are not limitedto, pharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active compounds,the liquid dosage forms may contain inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, cyclodextrins, dimethylformamide, oils (inparticular, cottonseed, groundnut, corn, germ, olive, castor, and sesameoils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols andfatty acid esters of sorbitan, and mixtures thereof. Besides inertdiluents, the oral compositions can also include adjuvants such aswetting agents, emulsifying and suspending agents, sweetening,flavoring, and perfuming agents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables. Theinjectable formulations can be sterilized, for example, by filtrationthrough a bacterial-retaining filter, or by incorporating sterilizingagents in the form of sterile solid compositions which can be dissolvedor dispersed in sterile water or other sterile injectable medium priorto use. Compositions formulated for parenteral administration may beinjected by bolus injection or by timed push, or may be administered bycontinuous infusion.

In order to prolong the effect of a compound of the present invention,it is often desirable to slow the absorption of the compound fromsubcutaneous or intramuscular injection. This may be accomplished by theuse of a liquid suspension of crystalline or amorphous material withpoor water solubility. The rate of absorption of the compound thendepends upon its rate of dissolution that, in turn, may depend uponcrystal size and crystalline form. Alternatively, delayed absorption ofa parenterally administered compound form is accomplished by dissolvingor suspending the compound in an oil vehicle. Injectable depot forms aremade by forming microencapsule matrices of the compound in biodegradablepolymers such as polylactide-polyglycolide. Depending upon the ratio ofcompound to polymer and the nature of the particular polymer employed,the rate of compound release can be controlled. Examples of otherbiodegradable polymers include poly(orthoesters) and poly(anhydrides).Depot injectable formulations are also prepared by entrapping thecompound in liposomes or microemulsions that are compatible with bodytissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or Vagina cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents such as phosphates orcarbonates.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like. The solid dosage forms of tablets, dragees, capsules, pills,and granules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes. Solid compositions of a similartype may also be employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polyethylene glycols and the like.

The active compounds can also be in micro-encapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluent such as sucrose, lactose or starch. Such dosage forms may alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may also comprisebuffering agents. They may optionally contain opacifying agents and canalso be of a composition that they release the active ingredient(s)only, or preferentially, in a certain part of the intestinal tract,optionally, in a delayed manner. Examples of embedding compositions thatcan be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, ear drops, and eye drops are also contemplatedas being within the scope of this invention. Additionally, the presentinvention contemplates the use of transdermal patches, which have theadded advantage of providing controlled delivery of a compound to thebody. Such dosage forms can be made by dissolving or dispensing thecompound in the proper medium. Absorption enhancers can also be used toincrease the flux of the compound across the skin. The rate can becontrolled by either providing a rate controlling membrane or bydispersing the compound in a polymer matrix or gel.

Formulation of an antibody or fragment to be administered will varyaccording to the route of administration and formulation (e.g.,solution, emulsion, capsule) selected. An appropriate pharmaceuticalcomposition comprising an antibody or functional fragment thereof to beadministered can be prepared in a physiologically acceptable vehicle orcarrier. A mixture of antibodies and/or fragments can also be used. Forsolutions or emulsions, suitable carriers include, for example, aqueousor alcoholic/aqueous solutions, emulsions or suspensions, includingsaline and buffered media. Parenteral vehicles can include sodiumchloride solution, Ringer's dextrose, dextrose and sodium chloride,lactated Ringer's or fixed oils. A variety of appropriate aqueouscarriers are known to the skilled artisan, including water, bufferedwater, buffered saline, polyols (e.g., glycerol, propylene glycol,liquid polyethylene glycol), dextrose solution and glycine. Intravenousvehicles can include various additives, preservatives, or fluid,nutrient or electrolyte replenishers (See, generally, Remington'sPharmaceutical Science, 16th Edition, Mack, Ed. 1980). The compositionscan optionally contain pharmaceutically acceptable auxiliary substancesas required to approximate physiological conditions such as pH adjustingand buffering agents and toxicity adjusting agents, for example, sodiumacetate, sodium chloride, potassium chloride, calcium chloride andsodium lactate. The antibodies and fragments of this invention can belyophilized for storage and reconstituted in a suitable carrier prior touse according to art-known lyophilization and reconstitution techniques.The optimum concentration of the active ingredient(s) in the chosenmedium can be determined empirically, according to procedures well knownto the skilled artisan, and will depend on the ultimate pharmaceuticalformulation desired. For inhalation, the antibody or fragment can besolubilized and loaded into a suitable dispenser for administration(e.g., an atomizer, nebulizer or pressurized aerosol dispenser).

The antibody or fragment can be administered in a single dose ormultiple doses. The dosage can be determined by methods known in the artand is dependent, for example, upon the antibody or fragment chosen, thesubject's age, sensitivity and tolerance to drugs, and overallwell-being. Antibodies and antigen-binding fragments thereof, such ashuman, humanized and chimeric antibodies and antigen-binding fragmentscan often be administered with less frequency than other types oftherapeutics. For example, an effective amount of an antibody can rangefrom about 0.01 mg/kg to about 5 or 10 mg/kg administered daily, weekly,biweekly or monthly.

The present invention provides new combination therapies for thetreatment of hematological malignancies. As used herein, the term“hematological malignancies” includes any malignancy associated withcells in the bloodstream; bone marrow; and the lymphoid system includingin the liver, spleen, and lymph nodes. Nonlimiting examples ofhematological malignancies include B and T cell lymphomas and leukemias.Nonlimiting examples of B and T cell lymphomas include, for example, lowgrade/follicular non-Hodgkin's lymphoma (NHL), small lymphocytic (SL)NHL, T or B prolymphocytic leukemia, diffuse large B cell NHL,peripheral T cell lymphomas, mantle cell lymphoma, marginal zonelymphomas, B or T cell lymphoblastic lymphoma, Burkitt's lymphoma,primary thyroid lymphoma, Waldenstrom's Macroglobulinemia orlymphoplamacytic lymphoma. Nonlimiting examples of leukemia include, forexample, chronic leukocytic leukemia, acute myelogenous leukemia (AML),acute lymphoblastic leukemia, chronic lymphocytic leukemia (CLL),chronic myelogenous leukemia, lymphoblastic leukemia, lymphocyticleukemia, monocytic leukemia, myelogenous leukemia and promyelocyticleukemia. Nonlimiting examples of hematological malignanciesadditionally include, for example, multiple myeloma, myelodysplasticsyndromes (MDS), including refractory anemia (RA), refractory anemiawith ringed siderblasts (RARS), (refractory anemia with excess blasts(RAEB), and RAEB in transformation (RAEB-T); and myeloproliferativesyndromes. It should be clear to those of skill in the art that thesepathological conditions may often have different names due todiffering/changing classification systems.

In some embodiments, the hematological malignancy to be treated by themethod of the invention is one in which the activity of an Aurora kinaseis amplified and in which the CD20 antigen is expressed. In someembodiments, the hematological malignancy is selected from the groupconsisting of lymphoma, leukemia and multiple myeloma. In certainembodiments, the lymphoma is selected from the group consisting of Bcell lymphoma, non-Hodgkin's lymphoma and mantle cell lymphoma.

The term “patient”, as used herein, means an animal, preferably amammal, more preferably a human. In some embodiments, the patient hasbeen treated with an agent, e.g., an Aurora kinase inhibitor or ananti-CD20 antibody, prior to initiation of treatment according to themethod of the invention. In some embodiments, the patient is a patientat risk of developing or experiencing a recurrence of a hematologicalmalignancy.

The expression “therapeutically effective amount” refers to an amount ofa drug substance (e.g., Aurora kinase inhibitor and/or anti-CD20antibody) effective for treatment or prophylaxis or amelioration ofsymptoms of a hematological malignancy discussed herein.

Compositions for use in the method of the invention may be formulated inunit dosage form for ease of administration and uniformity of dosage.The expression “unit dosage form” as used herein refers to a physicallydiscrete unit of agent appropriate for the patient to be treated. Itwill be understood, however, that the total daily usage of the compoundsand compositions of the present invention w111 be decided by theattending physician within the scope of sound medical judgment. A unitdosage form for parenteral administration may be in ampoules or inmulti-dose containers.

The Aurora kinase inhibitor may be administered with the anti-CD20antibody in a single dosage form or as a separate dosage form. Whenadministered as a separate dosage form, the anti-CD20 antibody may beadministered prior to, at the same time as, or following administrationof the Aurora kinase inhibitor of the invention.

As specifically contemplated herein, the instant invention includes thefollowing methods: A method to treat a patient suffering from ahematological malignancy comprising administering to said patient atherapeutically effective amount of a Aurora kinase inhibitorsimultaneously with or consecutively with (e.g., before or after) ananti-CD20 antibody; A method to treat a patient suffering from ahematological malignancy comprising administering to said patient atherapeutically effective amount of a Aurora kinase inhibitorsimultaneously with or consecutively with (e.g. before or after)rituximab; A method to treat a patient suffering from lymphomacomprising administering to said patient a therapeutically effectiveamount of a Aurora kinase inhibitor simultaneously with or consecutivelywith (e.g. before or after) an anti-CD20 antibody; A method to treat apatient suffering from lymphoma comprising administering to said patienta therapeutically effective amount of a Aurora kinase inhibitorsimultaneously with or consecutively with (e.g. before or after)rituximab; A method to treat a patient suffering from leukemiacomprising administering to said patient a therapeutically effectiveamount of a Aurora kinase inhibitor simultaneously with or consecutivelywith (e.g. before or after) an anti-CD20 antibody; A method to treat apatient suffering from leukemia comprising administering to said patienta therapeutically effective amount of a Aurora kinase inhibitorsimultaneously with or consecutively with (e.g. before or after)rituximab; A method to treat a patient suffering from multiple myelomacomprising administering to said patient a therapeutically effectiveamount of a Aurora kinase inhibitor simultaneously with or consecutivelywith (e.g. before or after) an anti-CD20 antibody; and A method to treata patient suffering from multiple myeloma comprising administering tosaid patient a therapeutically effective amount of a Aurora kinaseinhibitor simultaneously with or consecutively with (e.g. before orafter) rituximab.

In some particular embodiments, the method of the invention comprisesadministering to a patient suffering from a hematological malignancy atherapeutically effective amount of an Aurora kinase inhibitor ofFormula (I), (II) or (III) as defined herein simultaneously with orconsecutively with (e.g., before or after) rituximab.

Additionally, the invention relates to use of an Aurora kinase inhibitorfor the manufacture of a medicament for the treatment of a hematologicalmalignancy. In other particular embodiments, the invention relates tothe use of an Aurora kinase inhibitor of Formula (I), (II) or (III) asdefined herein, in the manufacture of a medicament for use incombination therapy with rituximab for the treatment of a hematologicalmalignancy.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meanings as commonly understood by one of ordinary skillin the art to which this invention belongs. Although any methods andmaterials similar or equivalent to those described herein can be used inthe practice or testing of the present invention, the preferred methods,devices and materials are herein described. All publications mentionedherein are hereby incorporated by reference in their entirety for thepurpose of describing and disclosing the materials and methodologiesthat are reported in the publication which might be used in connectionwith the invention.

EXAMPLES Definitions

-   -   ANOVA Analysis of variance    -   ΔAUC difference in the area under the curve    -   BID twice daily    -   DLBCL diffuse large B-cell lymphoma    -   IV intravenous(ly)    -   MTD maximum tolerated dose    -   SCID severe combined immunodeficiency    -   po. Orally (by mouth, per os)    -   QD once daily    -   QW or Q7D once weekly    -   SC subcutaneous(ly)    -   TG treatment group    -   TGI tumor growth inhibition

Experimental Overview

The Ly19-Luc, WSU-DLBCL2-Luc and PHTX-22-06 models described in thesestudies are human DLBCL cell lines, transfected with luciferase. Thesemodels were grown in immunocompromised mice subcutaneously on the flank,or disseminated throughout the body by tail vain injection.4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoicacid (III-1) was administered orally in both daily and twice dailydosing regimens and rituximab was administered by IV injection QD7×3.The efficacy, tumor growth and post-treatment survival of mice treatedwith Compound III-4 and rituximab were compared as single agents or incombination.

Sub-Cutaneous Models Example 1 Combination of Aurora A Kinase SpecificInhibitor (Compound III-1) and Rituximab in a Sub-Cutaneous Ly19Lymphoma Model Grown in Female SCID Mice Experimental Overview

This is an in vivo experiment looking at tumor volume after treatmentwith the combination of Compound III-1 and rituximab. Tumor growth wasmonitored with vernier calipers. The mean tumor volume was calculatedusing the formula V=W²×L/2. When the mean tumor volume reachedapproximately 200 mm³, the animals were randomized into the followingeight treatment groups, with each cohort made up of ten mice:

Vehicle

3 mg/kg Compound III-1 (qd)

10 mg/kg Compound III-1 (qd)

10 mg/kg Compound III-1 (bid)

10 mg/kg rituximab (qw)

3 mg/kg Compound III-1 (qd)+10 mg/kg rituximab (qw)

10 mg/kg Compound III-1 (qd)+10 mg/kg rituximab (qw)

10 mg/kg Compound III-1 (bid)+10 mg/kg rituximab (qw)

The animals were inoculated with 4.0×10⁶ cells from cell line Ly-19 atimplant site Flank (cell suspension). Compounds were administered for 21days, and tumor volumes were measured on days 0, 5, 13, 15, 18, and 21.After treatment ended, the surviving mice continued to be evaluated ondays 25, 28, 33, 36, 40, 43, 47, 50, 54, 60, and 62.

There were several endpoints in this experiment. The primary goal was todetermine whether the combination of Compound III-1 and rituximab wasmore effective at reducing tumor volume than either treatment alone. Thesecond endpoint was to evaluate the rates of tumor regrowth among thegroups after treatment was completed.

Statistical Methodology

Statistical analysis was performed using a linear mixed effectsregression model. This model takes into account the differences intrends of tumor growth between control and treated samples. Thestatistical modeling was conducted in two steps: model fitting and modelselection. In the first step, a family of ten closely relatedmixed-effects regression models was fitted to the study data. Data fromall time points in the study were used, including mice that weresacrificed before the end of the study. Each treatment group was fittedto a quadratic trend line for tumor growth that consisted of up to threeterms for tumor growth: zero-order (intercept), first-order (slope) andsecond-order (curvature). Each drug treatment was then modeled by up totwo interaction terms, one describing the difference in slope and theother describing the difference in curvature due to drug treatments. Inaddition, mouse-specific variability was accounted for by includingrandom effects for each mouse with up to three terms: a mouse-specificintercept, slope or curvature effect. Repeated measurements of tumorgrowth for a given mouse were modeled using a compound symmetrycovariance structure.

Model selection was performed by first filtering models that themodel-fitting algorithm was unable to fit in a numerically stable way(specifically by removing models that demonstrated sensitivity to thestarting value of the autocorrelation coefficient, and those for whomthe variance-covariance matrix of random effects was not positivedefinite). The best fit model was then selected using a statisticalcriterion called the Bayes Information Criterion (BIC), which is ameasure of a model's goodness of fit that takes into account the numberof parameters used by the model and the magnitude of the residuals—thedifference between fitted and observed values. The BIC favors modelsthat are parsimonious and that fit the underlying data well.

The model fitting and selection procedure were performed twice, once onthe original (untransformed) data, and once on log₁₀-transformed data.Once the automated model-fitting and selection procedure were completed,two best-fit models were generated, one on log-transformed data and theother on untransformed data. An investigator then studied the diagnosticplots generated by the two statistical models and chose one of them asthe appropriate model for the study. This choice was made on the basisof the distribution of the residuals as well as their behavior withrespect to the fitted values. Obvious trends in the residuals wereindicative of a poor model fit, suggesting trends remaining in the datathat the model had failed to take into account.

Once an appropriate statistical model was selected, the effect size wascalculated as the difference between areas under the model-fitted curves(ΔAUC) for treated and control groups, relative to the area under themodel-fitted curve for the control group. A MAUL of 0 meant that thecurves for the treatment and control groups were the same, whereas anegative ΔAUC indicated tumor growth inhibition upon treatment.

The significance of an effect size for a given pairwise comparison wasassessed using permutation analysis. During this procedure, theassignment of mice to treatment and control groups were randomlyshuffled. The ΔAUC metric was calculated for comparisons between thesenew simulated groups, and the process was repeated ˜2000 times. Thisgave rise to an empirical distribution of the ΔAUC values for the nullhypothesis, which stated that there was no difference in ΔAUC valuesbetween treatment and control groups. The reported p-value was theproportion of permuted ΔAUC values which were greater than the ΔAUC ofthe original group assignments. P-values <0.05 were consideredsignificant.

For combination studies a synergy measure was also reported (in additionto the measures of tumor growth inhibition for each arm of the trialrelative to control). For the synergy measure, the approach and theresults described here were essentially equivalent, except that effectsize was defined differently and permutation testing was performed overfour groups rather than two. The effect size for combinations wasdefined as:ΔAUC=[AUC_(AxB)−AUC_(ctl)−(AUC_(A)−AUC_(ctl)+AUC_(B)−AUC_(ctl))]/AUC_(ctl)(where AxB is the combination treatment, ctl is the control, and A and Bare the agents used singly). A ΔAUC of less than zero meant that acombination treatment led to a greater decrease in area under the curvethan the sum of individual treatments, indicating a synergistic tumorgrowth inhibition. Permutation testing was performed to compare thedifference between control and combination treatment against thedifference that would have been observed if the treatments were purelyadditive. Synergy measures disclosed herein are provided based on ΔAUCcalculations and based on TGI calculations. Because ΔAUC calculationscapture the entire treatment period within an experiment, suchcalculations are deemed more comprehensive and more accurate than theTGI calculations.

Results

In this study, all animals in all of the treatment groups endured the 21days of treatment.

The average tumor volume in the vehicle group increased almost sixteenfold from 180 mm³ at day 0 to over 2850 mm³ on day 21, and this resultedin a mean area under the log(fold change) over time curve (AUC) of 12.9.The AUCs, and therefore the tumor volumes, were smaller in each of thetreatment groups compared to vehicle (Table 3a). The results of thelinear regression model revealed that all of these differences relativeto the vehicle group were significant (Table 3b).

TABLE 3a Efficacy Analysis (Days 0 through 21) Pct Decrease in AUCRelative to Mean Vehicle Treatment AUC Vehicle — Compound III-1 (3 mg/kgqd) 22.9 Compound III-1 (10 mg/kg qd) 79.3 Compound III-1 (10 mg/kg bid)105.6 Rituximab (10 mg/kg) 71.8 Compound III-1 (3 mg/kg qd) + Rituximab130.0 (10 mg/kg) Compound III-1 (10 mg/kg qd) + Rituximab 151.4 (10mg/kg) Compound III-1 (10 mg/kg bid) + Rituximab 186.2 (10 mg/kg)Average percent change in the area under the log₁₀ fold change vs daycurves (AUC) relative to the mean AUC of the vehicle group.

TABLE 3b Efficacy Analysis (Days 0 through 21) Treatment Group ReferenceP-value Compound III-1 (3 mg/kg qd) Vehicle <0.01 Compound III-1 (10mg/kg qd) <0.01 Compound III-1 (10 mg/kg bid) <0.01 Rituximab (10 mg/kg)<0.01 Compound III-1 (3 mg/kg qd) + Rituximab <0.01 (10 mg/kg) CompoundIII-1 (10 mg/kg qd) + Rituximab <0.01 (10 mg/kg) Compound III-1 (10mg/kg bid) + Rituximab <0.01 (10 mg/kg) Compound III-1 (3 mg/kg) +Rituximab Compound III-1 <0.01 (10 mg/kg) (3 mg/kg) Rituximab <0.01 (10mg/kg) Compound III-1 (10 mg/kg qd) + Rituximab Compound III-1 <0.01 (10mg/kg) (10 mg/kg qd) Rituximab <0.01 (10 mg/kg) Compound III-1 (10 mg/kgbid) + Rituximab Compound III-1 <0.01 (10 mg/kg) (10 mg/kg bid)Rituximab <0.01 (10 mg/kg) Summary of mixed-effects linear regressionresults.

The three combination groups showed consistent decreases in tumor volumeand were all significantly lower than their respective single agentsalone. The Compound III-1 (3 mg/kg qd)+rituximab (10 mg/kg) group wassynergistic, while the other two combinations were additive whenexamining AUC values (Table 4). All three combinations were sub-additivewhen looking at tumor growth inhibition (Table 5, Table 6).

TABLE 4 Synergy Analysis (AUC, Days 0 through 21) Synergy 95% ConfidenceCombination Score Interval Assessment Compound III-1 −0.35 (−0.55,−0.15) Synergistic (3 mg/kg qd) + Rituximab (10 mg/kg) Compound III-10.00 (−0.19, 0.18) Additive (10 mg/kg qd) + Rituximab (10 mg/kg)Compound III-1 −0.09 (−0.32, 0.14) Additive (10 mg/kg bid) + Rituximab(10 mg/kg) Synergistic: score < 0, Additive: score = 0, Sub-additive:score > 0. Assessment based on whether 95% confidence interval includedthe value 0.

TABLE 5 Tumor Growth Inhibition (Day 21) Pct Tumor Growth InhibitionTreatment Relative to Vehicle Mean Vehicle — Compound III-1 (3 mg/kg qd)54.7 Compound III-1 (10 mg/kg qd) 97.1 Compound III-1 (10 mg/kg bid)102.2 Rituximab (10 mg/kg) 94.5 Compound III-1 (3 mg/kg qd) + Rituximab103.7 (10 mg/kg) Compound III-1 (10 mg/kg qd) + Rituximab 105.3 (10mg/kg) Compound III-1 (10 mg/kg bid) + Rituximab 105.8 (10 mg/kg)Average percent decrease in tumor growth relative to the mean tumorvolume of the vehicle group.

TABLE 6 Synergy Analysis (Tumor Growth Inhibition, Day 21 95% SynergyConfidence Combination Score Interval Assessment Compound III-1 (3 mg/kgqd) + 0.46 (0.35, 0.56) Sub-Additive Rituximab (10 mg/kg) Compound III-1(10 mg/kg qd) + 0.86 (0.81, 0.91) Sub-Additive Rituximab (10 mg/kg)Compound III-1 (10 mg/kg bid) + 0.91 (0.86, 0.96) Sub-Additive Rituximab(10 mg/kg) Synergistic: score < 0, Additive: score = 0, Sub-additive:score > 0. Assessment based on whether 95% confidence interval includedthe value 0.

To determine if tumors began to regrow after treatment ended,mixed-effects piecewise linear regression models were built to comparethe slope of the log tumor volume between days 9 and day 21 to the slopebetween days 21 and 62 (or earlier if all animals in a group died). Allof the examined groups showed increases in slope after treatment whichwere at least marginally significant (Table 7), suggesting that tumorvolumes stopped shrinking or, in the cases of Compound III-1 (10 mg/kgqd) and rituximab (10 mg/kg), began to grow again.

TABLE 7 Difference in Tumor Growth Rates Change in Treatment Group SlopeP-value Compound III-1 (10 mg/kg qd) 0.040 0.05 Compound III-1 (10 mg/kgbid) 0.018 <0.01 Rituximab (10 mg/kg) 0.039 <0.01 Compound III-1 (3mg/kg qd) + Rituximab 0.012 0.02 (10 mg/kg) Compound III-1 (10 mg/kgqd) + Rituximab 0.053 <0.01 (10 mg/kg) Compound III-1 (10 mg/kg bid) +Rituximab 0.091 <0.01 (10 mg/kg) Breakpoint was set at day 21. Change inslope was calculated as slope (day 21 to 62) − slope (day 13 to 21).P-values <0.05 indicate that the difference in slope was significantlydifferent than zero.

Conclusions

The effects of Compound III-1 in combination with rituximab upon tumorvolumes were investigated in an in vivo sub-cutaneous xenograft study. 3mg/kg Compound III-1 dosed qd, 10 mg/kg Compound III-1 dosed qd, and 10mg/kg Compound III-1 dosed bid were administered as both single agentsand in combination with 10 mg/kg of rituximab. All treatment groups hadsignificantly lower mean areas under the log(fold change) vs time curvesrelative to the vehicle group during the first 21 days. Additionally,the mean AUC of the 3 mg/kg Compound III-1 rituximab combination groupwas significantly lower than that for the respective individualtreatment groups. Surprisingly, the combination of Compound III-1 withrituximab was demonstrated to have a synergistic therapeutic effect inthis sub-cutaneous lymphoma model. Once treatment was completed, tumorvolumes ceased to continue diminishing, and in some cases began toregrow.

Example 2 Combination of Aurora A Kinase Specific Inhibitor (CompoundIII-1) and Rituximab in a Subcutaneous WSU-Luc Lymphoma Model Grown inFemale SCID Mice Experimental Overview

This is an in vivo experiment looking at tumor volume after treatmentwith the combination of Compound III-1 and rituximab. Tumor growth wasmonitored with vernier calipers. The mean tumor volume was calculatedusing the formula V=W²×L/2. When the mean tumor volume reachedapproximately 250 mm³, the animals were randomized into the followingsix treatment groups, with each group made up of ten mice:

Vehicle

3 mg/kg Compound III-1 (P.O., qd)

10 mg/kg Compound III-1 (P.O., qd)

10 mg/kg rituximab (I.V., q7d)

3 mg/kg Compound III-4+10 mg/kg rituximab

10 mg/kg Compound III-1+10 mg/kg rituximab

The animals were inoculated with 4.0×10⁶ cells from cell line WSU-DLCL2at implant site Flank (cell suspension). Compounds were administered for21 days, and tumor volumes were measured on days 0, 4, 7, 11, 15, 18,and 20. The primary goal was to investigate whether the combination ofCompound III-4 and Rituximab was synergistic.

Statistical Methodology

The statistical methodology used in these experiments was the same asthat described in Example 1 above.

Results

The average tumor volume in the vehicle group increased over nine-foldfrom 201 mm³ at day 0 to 1903 mm³ on day 20. The tumor volumes weresmaller in each of the treatment groups compared to vehicle (Table 8).

TABLE 8 Efficacy Analysis (Days 0 through 20) Pct Decrease in AUCRelative to Mean Treatment Vehicle AUC Vehicle — Compound III-1 (3mg/kg, PO, qd) 19.4 Compound III-1 (10 mg/kg, PO, 48.5 qd) Rituximab (10mg/kg, IV, q7d) 43.2 Compound III-1 (3 mg/kg) + 60.5 Rituximab (10mg/kg, IV, q7d) Compound III-1 (10 mg/kg) + 86.6 Rituximab (10 mg/kg,IV, q7d) Average percent change in the area under the log₁₀ fold changevs day curves (AUC) relative to the mean AUC of the vehicle group.

Both combination groups were additive relative to their respectiveindividual treatments when comparing AUC values (Table 9).

TABLE 9 Synergy Analysis of AUC values (Days 0 through 20) Approx. 95%Synergy Confidence Combination Score Interval Assessment Compound III-1(3 mg/kg) + 0.02 (−0.12, 0.16) Additive Rituximab (10 mg/kg, IV, q7d)Compound III-1 (10 mg/kg) + 0.05 (−0.08, 0.18) Additive Rituximab (10mg/kg, IV, q7d) Synergistic: score < 0, Additive: score = 0,Sub-additive: score > 0. Assessment based on whether 95% confidenceinterval included the value 0

Both treatment groups were sub-additive when looking at tumor growthinhibition (Table 10, and Table 11).

TABLE 10 Tumor Growth Inhibition (Day 20) Pct Tumor Growth InhibitionTreatment Relative to Vehicle Mean Vehicle — Compound III-1 (3 mg/kg,PO, qd) 33.1 Compound III-1 (10 mg/kg, PO, qd) 68.9 Rituximab (10 mg/kg,IV, q7d) 67.1 Compound III-1 (3 mg/kg) + 78.5 Rituximab (10 mg/kg, IV,q7d) Compound III-1 (10 mg/kg) + 95.5 Rituximab (10 mg/kg, IV, q7d)Average percent decrease in tumor growth relative to the mean tumorvolume of the vehicle group.

TABLE 11 Synergy Analysis of Tumor Growth Inhibition (Day 20) Approx.95% Synergy Confidence Combination Score Interval Assessment Compound (3mg/kg) + 0.21 (0.08, 0.35) Sub-Additive Rituximab (10 mg/kg, IV, q7d)Compound (10 mg/kg) + 0.40 (0.30, 0.51) Sub-Additive Rituximab (10mg/kg, IV, q7d) Synergistic: score < 0, Additive: score = 0,Sub-additive: score > 0. Assessment based on whether 95% confidenceinterval included the value 0.

Conclusions

The effects of Compound III-1 in combination with rituximab upon tumorvolumes were investigated in an in vivo sub-cutaneous xenograft study. 3mg/kg and 10 mg/kg Compound III-1, dosed PO and qd, and 10 mg/kgrituximab, dosed IV and q7d, were administered as both single agents andin combination. Neither combination group showed a synergisticinteraction relative to their respective single agents when looking atAUC or tumor growth inhibition.

Example 3 Combination of Aurora A Kinase Specific Inhibitor (CompoundIII-1) and Rituximab in a Sub-Cutaneous Primary Diffuse Large B-CellLymphoma Model (PHTX-22-06) Grown in Female SCID Mice ExperimentalOverview

This is an in vivo experiment looking at tumor volume after treatmentwith the combination of Compound III-1, and rituximab. Tumor growth wasmonitored with vernier calipers. The mean tumor volume was calculatedusing the formula V=W²×L/2. When the mean tumor volume reachedapproximately 200 mm³, the animals were randomized into the followingsix treatment groups, with each group made up of ten mice:

Vehicle

10 mg/kg Compound III-4 (P.O., bid)

20 mg/kg Compound III-1 (P.O., bid)

10 mg/kg rituximab (I.V., q7d)

10 mg/kg Compound III-1+10 mg/kg rituximab

20 mg/kg Compound III-1+10 mg/kg rituximab

The animals were inoculated with 2×5 mm³ tumor mass from primaryPHTX-22L-6 tumor chunk at implant site Flank (trocar). Compounds wereadministered for 21 days, and tumor volumes taken on days 0, 3, 7, 10,14, 17, 21, 24, and 27 were analyzed. The primary goal was toinvestigate whether the combination of Compound III-1 and rituximab wassynergistic.

Statistical Methodology

The statistical methodology used in these experiments was the same asthat described in Example 1 above.

Results

The average tumor volume in the vehicle group increased over nine-foldfrom 268 mm³ at day 0 to 2563 mm³ on day 27. The tumor volumes weresmaller in each of the treatment groups compared to vehicle (Table 12).

TABLE 12 Efficacy Analysis (Days 0 through 27) Pct Decrease in AUCRelative to Mean Treatment Vehicle AUC Vehicle — Compound III-1 (10mg/kg, PO, bid) 52.3 Compound III-1 (20 mg/kg, PO, bid) 79.3 Rituximab(10 mg/kg, IV, q7d) 41.9 Compound III-1 (10 mg/kg) + Rituximab (10mg/kg, 75.8 IV, q7d) Compound III-1 (20 mg/kg) + Rituximab (10 mg/kg,146.8 IV, q7d) Average percent change in the area under the log₁₀ foldchange vs day curves (AUC) relative to the mean AUC of the vehiclegroup.

Both combinations groups were additive relative to their respectiveindividual treatments when comparing AUC values (Table 13).

TABLE 13 Synergy Analysis of AUC values (Days 0 through 27) Approx. 95%Synergy Confidence Combination Score Interval Assessment Compound III-1(3 mg/kg) + 0.18 (−0.05, 0.42) Additive Rituximab (10 mg/kg, IV, q7d)Compound III-1 (10 mg/kg) + −0.26 (−0.80, 0.29) Additive Rituximab (10mg/kg, IV, q7d) Synergistic: score < 0, Additive: score = 0,Sub-additive: score > 0. Assessment based on whether 95% confidenceinterval included the value 0.

Both treatment groups were sub-additive when looking at tumor growthinhibition (Table 14, and Table 15).

TABLE 14 Tumor Growth Inhibition (Days 0 through 27) Pct Tumor GrowthInhibition Treatment Relative to Vehicle Mean Vehicle — Compound III-1(10 mg/kg, PO, bid) 86.3 Compound III-1 (20 mg/kg, PO, bid) 95.1Rituximab (10 mg/kg, IV, q7d) 57.3 Compound III-1 (10 mg/kg) + 97.3Rituximab (10 mg/kg, IV, q7d) Compound III-1 (20 mg/kg) + 105.1Rituximab (10 mg/kg, IV, q7d) Average percent decrease in tumor growthrelative to the mean tumor volume of the vehicle group.

TABLE 15 Synergy Analysis of Tumor Growth Inhibition (Days 0 through 27)Approx. 95% Synergy Confidence Combination Score Interval AssessmentCompound III-1 (10 mg/kg) + 0.46 (0.26, 0.67) Sub- Rituximab (10 mg/kg,Additive IV, q7d) Compound III-1 (20 mg/kg) + 0.47 (0.27, 0.68) Sub-Rituximab (10 mg/kg, Additive IV, q7d) Synergistic: score < 0, Additive:score = 0, Sub-additive: score > 0. Assessment based on whether 95%confidence interval included the value 0.

Conclusions:

The effects of Compound III-4 in combination with rituximab upon tumorvolumes were investigated in an in vivo sub-cutaneous xenograft study.10 mg/kg and 20 mg/kg Compound dosed PO and bid, and 10 mg/kg rituximab,dosed IV and q7d, were administered as both single agents and incombination. Neither combination examined showed a synergisticinteraction relative to their respective single agents when looking atAUC or tumor growth inhibition, which may be attributable to thesignificant single agent activity observed in this model.

Disseminated Models Example 4 Combination of Aurora A Kinase SpecificInhibitor (Compound III-1) and Rituximab in a Disseminated LymphomaModel of Ly19-Luc Cell Line Grown in Female SCID Mice ExperimentalOverview

The in vivo experiments using the disseminated Ly19-Luc lymphoma modelwere performed in duplicate. The experiments consisted of looking attumor volume after treatment with the combination of Compound III-1 andrituximab. Tumor volumes were estimated once weekly throughout theinoculation and treatment period using the Xenogen IVIS® imaging system(Xenogen Corporation, Alameda, Calif.). To image the mice, anintraperitoneal (IP) injection of luciferase (15 mg/ml), wasadministered 10 minutes prior to procedure and mice were anesthetizedwith 2% isofluorane 2-5 minutes throughout the scanning procedure. ForXenogen imaging, each mouse was imaged on dorsal and ventral views. Thesum of 2 photon flux measurements was used for the analysis.

The antitumor effects of each treatment group were determined bycalculating the percent TGI ([Δ control mean tumor volume−Δ treated meantumor volume]×100/Δ control mean tumor volume) at the end of treatment.Mice were weighed once weekly for the duration of the study and themaximal percent body weight change was determined during the treatmentperiod. Animals were monitored for survival up to 132 days followingtreatment. Animals were removed from the study when they reached humaneendpoints (>20%, body weight loss or paralysis of either both front orhind limbs), the medial survival for each group was determined and thesurvival rate of treatment groups were compared to control. Treatmentgroups were evaluated to determine if the effects of combinationtreatment were synergistic, additive or sub-additive relative tocontrol.

Statistical Analysis

Tumor growth inhibition (TGI): The photon flux data was log₁₀transformed, and these values over the treatment period were comparedacross treatment groups to assess if the differences in the trends overtime were statistically significant. A mixed-effects linear regressionmodel using a restricted maximum likelihood was fit to the data. AnANOVA test was performed to determine if there was a statisticallysignificant difference between the treatment groups and control.

Area under the curve (AUC): Log₁₀-transformed fold change photon fluxvalues (tumor burden) from baseline were also used to calculate AUCvalues for each animal. The AUC values from the mice in a giventreatment group were then averaged together to generate mean AUC valuesand associated standard errors.

Synergy Effects: A synergy score calculation was used to address thequestion of whether the effects of the combination treatment weresynergistic, additive, or sub-additive relative to the individualtreatments. The effect of the combination treatment was consideredsynergistic if the synergy score was less than 0, additive if thesynergy score equaled 0, and sub-additive if the synergy score wasgreater than O, Standard errors and 95% confidence intervals (calculatedas 2*SE) were used to determine if the synergy scores were significantlydifferent from zero.

Tumor Regrowth: To compare the tumor regrowth rates after stoppingtreatment, mixed-effects piecewise linear regression models were builtseparately for each treatment group with mice monitored beyond treatmentperiod. All P-values <0.05 were called significant in this report.

Survival Rate: The survival rates of the animals in each treatment groupwere plotted using Kaplan-Meier curves and the log rank test was used tocompare survival rates among pairs of treatment groups.

Experiment #1 Disseminated Ly19-Luc Lymphoma Model

Animals bearing Ly19-Luc xenografts were treated with Compound III-1 andrituximab as single agents and in combination. The TGI, calculated onDay 24 was similar between treatment groups (89.6%-100.3%). Tumor growthwas significantly inhibited in all single agent and combinationtreatment groups compared to vehicle (p<0.001, Table 16).

TABLE 16 Dosing regimen for mice in first disseminated Ly19 experimentalgroup Maximum Survival Study/ Percent Body TGI Median Treatment DoseRoute and Weight Mean^(c) Survival Group^(a) (mg/kg)^(b) Dose RegimenChange (%) (%) p Value^(d) (Days) p Value^(e) Vehicle 0 Po/QD × 21 −5.9,Day 24 N/A N/A 25 N/A days Compound 3 Po/QD × 21 +6.2, Day 24 89.6, Day24 <0.001 40 <0.001 III-1 days Compound 10 Po/QD × 21 +3.3, Day 24  100,Day 24 <0.001 63.5 <0.001 III-1 days Compound 3 po/QD × 21 +8.7, Day 24 100, Day 24 <0.001 >100 <0.001* III-1 days Rituximab 10 IV/QW × 3 dosesCompound 10 po/QD × 21 +4.5, Day 24 100.3, Day 24  <0.001 >100 <0.001*III-1 days Rituximab 10 IV/QW × 3 doses Rituximab 10 IV/QW × 3 +9.4, Day24 99.6, Day 24 <0.001 66 <0.001 doses ^(a)There were 10 mice in eachtreatment group. ^(b)For each dose, mice received 100 μL of CompoundIII-1 and/or rituximab dosing solution prepared at 0.75, 2.5, 5.0 and7.5 mg/mL (3, 10, 20, 30 mg/kg Compound III-1) or 2.0 mg/mL (10 mg/kgrituximab). These dosing solutions were prepared routinely based onhistorical mouse body weights of 25 or 20 grams respectively. All doseswere approximate. ^(c)Mean tumor volumes, and TGI values were calculatedon Day 24 of treatment. ^(d)TGI = TGI calculation B − tumor growthinihibition (TGI = [(Δ control average volume − Δ treated averagevolume) × 100/Δ control average volume]. p values were calculated withan ANOVA, p < 0.05 considered statistically significant. TGI values willbe greater than 100% when the average volume of the treatment group issmaller at the end of treatment than at the beginning of treatment^(e)Log-rank analysis was used to compare the survival rate of eachtreatment group to the vehicle group test, p < 0.05 consideredstatistically significant. *= Combination treatment groups hadsignificantly longer survival than the corresponding individualtreatment groups (p ≦ 0.004). ^(f)Animals dosed with Compound III-1 at10 mg/kg BID and 30 mg/kg QD received a 5 day dose holiday from Day 13to Day 17. ^(g)The vehicle used in TG1 and the treatment groups was 10%HP-β-CD plus 1% NaHCO₃. The vehicle used in the rituximab treatmentgroups was 0.9% saline

Individual whole body bioluminescence images were taken of all mice inall treatment groups using the Xenogen IVIS® imaging system. Anybioluminescence observed in these whole body images represents tumorpresence in the mouse model. Tumor presence/growth in each mouse wasassessed using this system prior to treatment on Day 0; after the end oftreatment on Day 24; and of mice remaining in the study on Day 52. OnDay 24 there is a striking reduction in the fluorescent signal of thetumor as a result of treatment with Compound III-1 at 10 mg/kg, with thecombination Compound III-1 at 3 mg/kg with rituximab and with thecombination Compound III-1 at 10 mg/kg with rituximab. Mice receivingcombination treatments show little or no evidence of the disseminatedlymphoma tumor. At Day 52 however, tumor growth was evident in the miceremaining in the single agent Compound III-1 10 mg/kg and rituximab 10mg/kg groups.

Photon flux values (tumor burden) from baseline to Day 24 were also usedto calculate AUC values for each animal and the percent decrease in theAUC relative to the mean vehicle AUC was calculated (Table 17a). Asynergy score calculation was applied to the AUC data to determinewhether the effects of the combination treatment were synergistic,additive or sub-additive relative to the individual treatments. Thisanalysis showed that the combination treatment of Compound III-1 at 3mg/kg QD with rituximab at 10 mg/kg QW was synergistic when comparingthe log₁₀-transformed fold changes and the combination treatment ofCompound III-1 at 10 mg/kg with rituximab at 10 mg/kg QW displayed anadditive effect (Table 17b).

TABLE 17a Percent Decrease in AUC Relative to Treatment Mean Vehicle AUCVehicle N/A Compound III-1 (3 mg/kg-QD) 59.3 Compound III-1 (10mg/kg-QD) 108.2 Rituximab (10 mg/kg-QW) 103.3 Compound III-1 (3 mg/kg) +121.2 Rituximab (10 mg/kg) Compound III-1 (10 mg/kg) + 121.4 Rituximab(10 mg/kg) Average percent change in the area under the log₁₀ foldchange versus day curves (AUC) relative to the mean AUC of the vehiclegroup for each treatment group. Values greater than 100 indicatedecreased tumor burden.

TABLE 17b Synergy 95% Confidence Combination Score Interval AssessmentCompound III-1 (3 mg/kg) + −25.5 (−35.9, −15.0) Synergistic Rituximab(10 mg/kg) Compound III-1 (10 mg/kg) + −4.3 (−11.5, 2.9) AdditiveRituximab (10 mg/kg) Synergistic: score < 0, Additive: score = 0,Sub-Additive: score > 0. Assessment based on whether 95% confidenceinterval included the value 0.

All vehicle treated mice reached the pre-defined endpoint of paralysisand were euthanized between Day 21 and Day 31, however all mice in thetwo combination treatment groups were alive up to Day 132. By the end ofthe study (Day 132), the number of mice remaining in the single agentCompound III-1 3 mg/kg, Compound III-1 10 mg/kg and rituximab 10 mg/kggroups was 1 out of 10, 3 out of 10 and 1 out of 10 respectively. Themedian survival in days for each group is presented in Table 18. Logrank analysis, conducted to compare the survival rates between groups,showed that all treatment groups had significantly longer survival thanthe vehicle group, and all combination groups had significantly longersurvival than each of the individual treatments (Table 16). Table 16also shows the mean maximum body weight change of the groups from Day 0to Day 24. The maximum body weight loss for vehicle group was 5.9% onDay 24. All other treatment groups gained weight during the study,including the single agent and combination agent groups. Treatment withCompound III-1 at 3 or 10 mg/kg on a QD schedule or rituximab at 10mg/kg on a QW schedule was well tolerated.

TABLE 18 Method of Study/Cell Dose Administration/ NoteworthyLine/Treatment (mg/kg) Frequency Endpoints Findings Ly19-Luc 0 po/QD ×21 days TGI^(a) N/A Vehicle (10% HP-β-CD Median Survival (Days) 25 plus1% NaHCO₃) BW change^(b) −5.9, Day 24 Compound III-1 3 po/QD × 21 daysTGI 89.6, p < 0.001 Median Survival (Days) 40, p < 0.01^(c) BW change+6.2, Day 24 Compound III-1 10 po/QD × 21 days TGI 100, p < 0.001 MedianSurvival (Days) 63.5, p < 0.01 BW change +3.3%, Day 24 Compound III-1 +3 po/QD × 21 days TGI 100, p < 0.001 Rituximab 10 IV/QW × 3 doses MedianSurvival (Days) >100, p < 0.01 BW change +8.7%, Day 24 Compound III-1 +10 po/QD × 21 days TGI 100.3, p < 0.001 Rituximab 10 IV/QW × 3 dosesMedian Survival (Days) >100, p < 0.01 BW change +4.5%, Day 24 Rituximab10 IV/QW × 3 doses TGI 99.6, p < 0.001 Median Survival (Days) 66, p <0.01 BW change +9.4%, Day 24 ^(a)TGI was calculated on Day 24, p valueswere calculated using a one-way ANOVA with p < 0.05 consideredstatistically significant ^(b)Maximum body-weight change. ^(c)Log-rankanalysis was used to compare the survival rate of each treatment groupto the vehicle group, p < 0.05 considered statistically significant,

Experiment #2 Disseminated Ly19-Luc Lymphoma Model

Mice were dosed according to the following treatment groups:

TABLE 19 Dosing regimen for mice in second disseminated Ly19experimental group. Dose Dose Animals/ Dose Dose Dose Solution VolumeGroup Test Article group Route (mg/kg) Regimen (mg/ml) (ml) 1 Vehicle 10PO 0 QD 100 2 Compound 10 PO 3 QD 0.75 100 III-1 3 Compound 10 PO/IV3/10 QD/Q7D × 3 0.75/2.5 100 III-1 + Rituximab 4 Rituximab 10 IV 10 Q7D× 3 2.5 100 5 Rituximab 10 IV 5 Q7D × 3 1.25 100 6 Rituximab 10 IV 1 Q7D× 3 0.25 100 7 Rituximab 10 IV 0.5 Q7D × 3 0.025 100

Results

Mice were weighed and tumor volumes were estimated with Xenogen signal(average photon flux) calculation once a week throughout the inoculationand the treatment period and after the treatment until the end of study.

Treatment started 7 days following the inoculation of tumor cells intothe tail vein, with an average photon flux measurement of 1×10⁷ ontreatment Day 0. The TGI, calculated on Day 23 (2 days post dose) wassimilar between treatment groups (75.8-100%). Tumor growth wassignificantly inhibited (P<0.001) in all groups including the singleagents (Compound III-1 or rituximab) the combination of CompoundIII-1+rituximab treatment group when compared to control (Table 20).

TABLE 20 TGI, tumor growth inhibition (TGI = 100 − [(MTV treated/MTVcontrol) × 100]; Mean Group/Test Dose Route & Photon Flux TGI Article(mg/kg) N Schedule (Day 23) Day 23 P-value Group — 10 PO QD × 3 wks1.84E+09 — 1/Vehicle Group 3 mg/kg 10 PO QD × 3 wks 2.34E+08 87.7% P <0.001 2/Compound III-1 Group 3/ 3/10 mg/kg   10 PO QD × 3 wks 9.13E+05 100% P < 0.001 Compound IV Q7D × 3 wks III-1/ Rituximab Group 10 mg/kg 10 IV Q7D × 3 dose 8.43E+07 95.9% P < 0.001 4/Rituximab Group 5 mg/kg 10IV Q7D × 3 dose 1.57E+08 91.9% P < 0.001 5/Rituximab Group 1 mg/kg 10 IVQ7D × 3 dose 3.52E+08 81.3% P < 0.001 6/Rituximab Group 0.1 mg/kg   10IV Q7D × 3 dose 4.52E+08 75.8    P < 0.001 7/Rituximab P < 0.001 asdetermined by ANOVA

To better compare tumor growth and the response to treatment betweengroups, mean AUC values were calculated for each group based on photonflux levels representing tumor burden. The AUC values from each groupduring the treatment period up to Day 23 (2 days post-treatment) aresummarized in Table 21a.

TABLE 21a Mean Treatment AUC Vehicle 30.4 Rituximab (0.5 mg/kg Q7D) 24.7Rituximab (1 mg/kg Q7D) 18.8 Rituximab (5 mg/kg Q7D) 8.1 Rituximab (10mg/kg Q7D)) 8.4 Compound III-1 (3 mg/kg QD) 18.2 Compound III-1 (3 mg/kgQD + −20.0 Rituximab 10 mg/kg Q7D) Mean area under the log₁₀ fold changevs day curves (AUC) for each treatment group. Negative values indicatedecreased tumor burden.

Average photon flux measurements increased approximately two logs in thevehicle group during the 23-day period, which was an average increase intumor burden of nearly two-fold and resulted in a mean AUC of 30.4(Table 21a). The AUCs, and therefore the tumor burden, were smaller ineach of the treatment groups compared to vehicle. A clear dose responsein the AUC values was observed in the rituximab treatment groups. Theresults of the linear regression model revealed that all of thesedifferences relative to the vehicle group were significant (P<0.01,Table 21b). Additionally, the combination treatment group (CompoundIII-1 3 mg/kg+rituximab 10 mg/kg) showed a consistent decrease in tumorburden (−20.0), that was significantly lower than either of therespective single agents alone (Compound III-1 3 mg/kg and rituximab 10mg/kg, P<0.01). In fact, the mice in this group had photon flux valuesthat were in the un-inoculated, baseline range (photon flux=4−7×10̂5),suggesting the tumors had disappeared.

TABLE 21b Summary of mixed-effects linear regression results TreatmentGroup Reference P-value Compound III-1 (3 mg/kg-QD) Vehicle <0.01Rituximab (0.5 mg/kg Q7D) 0.02 Rituximab (1 mg/kg Q7D) 0.01 Rituximab (5mg/kg Q7D) <0.01 Compound III-1 (3 mg/kg QD) + <0.01 Rituximab (10 mg/kgQ7D) Compound III-1 (3 mg/kg QD) + Compound III-1 (3 mg/kg <0.01Rituximab (10 mg/kg Q7D) QD) Compound III-1 (3 mg/kg QD) + Rituximab (10mg/kg Q7D) <0.01 Rituximab (10 mg/kg Q7D)

A synergy score calculation was applied to these data to determinewhether the effects of the combination treatment were synergistic,additive or sub-additive relative to the individual treatments. Thisanalysis showed that the combination treatment with Compound III-1 at 3mg/kg plus rituximab at 10 mg/kg was synergistic when comparing thelog₁₀-transformed fold changes (Table 22).

TABLE 22 Synergy 95% Confidence Combination Score Interval AssessmentCompound III-1 (3 mg/kg + −46.6 (−56.2, −37.0) Synergistic Rituximab 10mg/kg Synergistic: score < 0, Additive: score = 0, Sub-Additive: score >0. Assessment based on whether 95% confidence interval included thevalue 0.

Following treatment, tumor growth was monitored in remaining mice up toDay 125 to determine if tumors would re-grow after treatment ended.Mixed-effects piecewise linear regression models were built to comparethe slope of the log flux between Days 9 and 23 to the slope betweenDays 23 and 125 (or earlier if all animals in a group died). Due to lossof mice from paralysis in many groups, only the combination CompoundIII-1 and rituximab group and the rituximab 10 and 5 mg/kg groups wereevaluated. None of the groups had significantly different changes inslopes after treatment stopped on Day 23 (Table 23), indicating thattumor growth/inhibition did not significantly change following thecessation of treatment. These data suggest that the inhibitory effectsof each of the respective treatments appear to continue up to 104 daysfollowing treatment.

TABLE 23 Breakpoint was set at Day 23. Difference was calculated asslope (Day 23 to 125) − slope (Day 9 to 23). Difference Treatment Groupin Slope P-value Rituximab (5 mg/kg) −0.01 0.49 Rituximab (10 mg/kg)−0.01 0.40 Compound III-1 (3 mg/kg + 0.00 0.86 Rituximab 10 mg/kg)P-values <0.05 indicate that the difference in slope was significantlydifferent than zero.

Individual whole body bioluminescence images were taken of all mice inall treatment groups using the Xenogen IVIS® imaging system. Tumorpresence/growth in each mouse was assessed using this system prior totreatment on Day 0; 3 days before the end of treatment (Day 18); and 104days following the end of treatment (Day 125). On Day 18 there is astriking reduction in the fluorescent signal of the tumor as a result oftreatment with the combination Compound III-1 at 3 mg/kg with rituximabas compared to any of the other treatment groups or control group. Micereceiving combination treatments show little or no evidence of thedisseminated lymphoma tumor, whereas tumor growth was evident in thesingle agent Compound III-1 3 mg/kg group and all of the single agentrituximab treatment groups. Bioluminescence images of mice in thecombination treatment group, i.e., Compound III-1 at 3 mg/kg withrituximab, on Day 125, show no evidence of tumor growth. Due to the lossof mice from paralysis in the other treatment groups, bioluminescenceimaging was not conducted in these groups.

All vehicle treated mice reached the pre-defined endpoint of paralysisand were euthanized between Day 21 and Day 31. A dose response wasobserved in the survival rate of rituximab treated mice with 3/10, 1/10,1/10 and 0/10 mice remaining by Day 125 in the 10, 5, 1 and 0.5 mg/kggroups respectively. Log rank analysis, conducted to compare thesurvival rates between groups, demonstrates that all treatment groupshad significantly longer survival than the vehicle group, and thecombination group had significantly longer survival than each of theindividual treatments. None of the mice in the combination treatmentgroup were removed during the 125 days of the study

Table 24 shows the mean maximum body weight change of the groups fromDay 0 to Day 22 of the study. The maximum body weight loss for vehiclegroup was 1.75% on Day 22. All other treatment groups gained weightduring the study, including the single agent and combination agentgroups. Treatment with Compound III-1 at 3 mg/kg on a QD schedule, orrituximab up to 10 mg/kg on a Q7D schedule, were well tolerated.

TABLE 24 Body weight (BW) change Mean Test Dose Route & BW Mean BWMaximum BW Article (mg/kg) N Schedule Day 0 Day 22 Change (%) Day 22Vehicle — 10 PO QD × 19.46 19.12 −1.75 3 wks Compound 3 mg/kg 10 PO QD ×19.20 19.81 +3.1 III-1 3 wks Compound 3 mg/kg 10 PO QD × 18.02 18.21+1.05 III-1/ 3 wks/ Rituximab 10 mg/kg  IV Q7D × 3 dose Rituximab 10mg/kg  10 IV Q7D × 3 19.11 19.72 +3.19 dose Rituximab 5 mg/kg 10 IV Q7D× 3 18.55 19.55 +5.39 dose Rituximab 1 mg/kg 10 IV Q7D × 3 19.43 20.25+4.22 dose Rituximab 0.5 mg/kg   10 IV Q7D × 3 19.30 20.27 +5.02 dose

Conclusions

In vivo imaging experiments in SCID mice bearing Ly19-Luc disseminatedlymphoma tumors were performed in duplicate in order to confirm theeffects of Compound III-1 and rituximab as single agents and ascombination treatment. Tumor burden and TGI were determined usingquantitative Xenogen imaging in mice receiving various doses of CompoundIII-1 with and without 10 mg/kg of rituximab. Tumor growth wassignificantly inhibited in all treatment groups (P<0.001). Tumor burden,presented as the AUC of photon flux values during the treatment period,was significantly lower in all treatment groups compared to control.Combination treatment with Compound III-1 at 3 mg/kg and rituximab at 10mg/kg appears to provide a synergistic effect that significantly loweredtumor burden when compared to either of the agents alone, therebycorroborating the synergistic effect observed in the sub-cutaneous Ly19lymphoma model discussed above (refer to Example 1). The survival of theanimals was significantly higher in each of the treatment groupscompared to the vehicle group and significantly higher in thecombination groups compared to the respective individual treatments.Following treatment, there were no significant changes in tumor growthrates in any of the groups up to 52 days in the first replicate and 125days in the second replicate. In summary, results from the twoexperiments are consistent with one another and these data confirm thata combination of Compound III-1 and rituximab is the most effectivetreatment for disseminated Ly19-Luc lymphoma in SCID mice, resulting ina reduction of tumor burden to undetectable levels.

Experiment 5 Combination of Aurora A kinase Specific Inhibitor (CompoundIII-1) and Rituximab in a Disseminated Lymphoma Model of WSU-DLBCL2-lucCell Line Grown in Female SCID Mice Experimental Overview

Two separate studies were conducted in the WSU-DLBCL2-luc model.Compound III-1 was administered initially at low doses (3 or 10 mg/kg ona QD schedule) alone and in combination with rituximab, or at higherdoses (10 or 20 mg/kg on a BID schedule) alone or in combination withrituximab. After treatment, animals were monitored up to Day 132 tocompare the survival between treatment groups and vehicle.

In the first WSU-DLBCL2 study, Compound III-4 when dosed alone at either3 mg/kg or 10 mg/kg QD did not significantly inhibit tumor growth inthis model (TGI=50.9%, p>0.05, TGI=88.2%, p>0.05 respectively).Rituximab dosed alone (10 mg/kg QW) or in combination with CompoundIII-1 at 3 or 10 mg/kg significantly inhibited tumor growth (TGI=83.6%,p<0.05, TGI=91.8%, p<0.05, TGI=99.0%, p<0.001 respectively) in SCID micebearing WSU-DLCL2-Luc xenografts (Table 25). In the second study, whenCompound III-1 was dosed alone at either 10 mg/kg or 20 mg/kg BID, tumorgrowth was significantly inhibited in this model (TGI=99.7%, p<0.001,for both groups). Rituximab dosed alone at 10 mg/kg QW (TGI=88.4%,p<0.001) and in combination with Compound III-4 at 10 or 20 mg/kg BIDresulted in significant tumor growth inhibition (TGI=99.6% and 99.9%respectively, p<0.001 for both), (Table 25).

TABLE 25 Tumor Growth Inhibition, Body Weight Change and SurvivalMaximum Percent Survival Body TGI Median Dose Route and Dose Weight pSurvival p (mg/kg)^(b) Regimen Change (%) Mean (%)^(c) Value^(d) (Days)Value^(d) 1st WSU- DLBCL2 Study/Treatment Group^(a) Vehicle^(f) 0 po/QD× 21 days −0.3, Day 21 N/A N/A 37 N/A Compound 3 po/QD × 21 days −3.1,Day 21 50.9, Day 21 >0.05 46.5 0.040 III-1 Compound 3 po/QD × 21 days−2.4, Day 21 91.8, Day 21 <0.05 73 0.003 III-1 10 IV/QW × 3 dosesRituximab Compound 10 po/QD × 21 days −4.5, Day 21 88.2, Day 21 >0.05 440.017 III-1 Compound 10 po/QD × 21 days −2.8, Day 21 99.0, Day 21 <0.00152.5 <0.001 III-1 10 IV/QW × 3 doses Rituximab Rituximab 10 IV/QW × 3doses +1.7, Day 21 83.6, Day 21 <0.05 61 <0.001 2nd WSU- DLBCL2 studyVehicle 0 po/BID × 21 days +2.5, Day 22 N/A N/A 45 N/A Compound 10po/BID × 21 days −3.9, Day 19 99.7, Day 22 <0.001 70 <0.001 III-1Compound 20 po/QD × 21 days −8.9, Day 9  99.7, Day 22 <0.001 111.5<0.001 III-1g Compound 10 po/BID × 21 days −1.7, Day 19 99.6, Day 22<0.001 121 <0.001 III-1 10 IV/QW × 3 doses Rituximab Compound 20 po/BID× 21 days −12.2, Day 9  99.9, Day 22 <0.001 >128 <0.001 III-1g 10 IV/QW× 3 doses Rituximab Rituximab 10 IV/QW × 3 doses +6.3, Day 22 88.4, Day22 <0.001 59 >0.05 ^(a)There were 10 mice in each treatment group.^(b)For each dose, mice received 100 μL of Compound III-1 and/orrituximab dosing solution prepared at 0.75, 2.5, 5.0 and 7.5 mg/mL (3,10, 20, 30 mg/kg Compound III-1) or 2.0 mg/mL (10 mg/kg rituximab).These dosing solutions were prepared routinely based on historical mousebody weights of 25 or 20 grams respectively. All doses were approximate.^(c)Mean tumor volumes, and TGI values were calculated on Day 21 (1^(st)study) and Day 22 (2^(nd) study) of treatment. ^(d)TGI = TGI calculationB − tumor growth inhibition (TGI = [(Δ control average volume − Δtreated average volume) × 100/Δ control average volume]. p values werecalculated with an ANOVA, p < 0.05 considered statistically significant^(e)Log-rank analysis was used to compare the survival rate of eachtreatment group to the vehicle group, p < 0.05 considered statisticallysignificant, ^(f)The vehicle used in TG1 and the treatment groups was10% HP-β-CD plus 1% NaHCO. The vehicle used in the rituximab treatmentgroups was 0.9% saline. ^(g)Animals dosed with Compound III-1 at 20mg/kg BID, and animals in the combination group dosed with 20 mg/kgCompound III-1 and rituximab at 10 mg/kg QW received a dose holiday for5 days, from Day 9 to Day 13.

After treatment, animals were monitored for survival up to Day 125(1^(st) study) or Day 130 (2^(nd) study). The median survival in daysfor each group is presented in Table 25 and the mean survival rate ofthe treatment groups were compared to the vehicle group. In the 1ststudy, all vehicle animals were euthanized at the humane endpoint(paralysis) by Day 44 and all treatment groups showed significantlylonger survival relative to the vehicle group (p<0.04-0.001, Table 25).By the end of the study (Day 125), 1 out of 10 mice remained in thesingle agent rituximab group and in the 10 mg/kg Compound III-1combination treatment group. In the 2^(nd) study, all vehicle animalswere euthanized at the humane endpoint by Day 68. With the exception ofrituximab treatment alone (p>0.05), all treatment groups showedsignificantly longer survival relative to the vehicle group (p<0.001,Table 25). The number of mice remaining at the end of the study (Day130) was 1 out of 10 in the 10 mg/kg single agent Compound III-1 andrituximab groups, 5 out of 10 in the 20 mg/kg Compound III-1 singleagent group and the 10 mg/kg Compound III-1 combination group, and 8 outof 10 mice in the mg/kg Compound III-1 combination group.

The tumor volumes were smaller in each of the treatment groups in thefirst study compared to vehicle (Table 26a). Both combinations groupswere additive relative to their respective individual treatments whencomparing AUC values (Table 26b).

TABLE 26a Area Under the Curve Efficacy and Synergy Analysis (Days 0Through 21) for first study. Average percent change in the area underthe log₁₀ photon flux vs day curves (AUC) relative to the mean AUC ofthe vehicle group. Pct Decrease in AUC Relative to Mean TreatmentVehicle AUC Vehicle — Compound III-1 (3 mg/kg, PO, QD) 21.1 CompoundIII-1 (10 mg/kg, PO, QD) 42.0 Rituximab 10 (mg/kg, IV, QW) 44.4 CompoundIII-1 (3 mg/kg) + 48.6 Rituximab (10 mg/kg) Compound III-1 (10 mg/kg) +75.0 Rituximab (10 mg/kg)

TABLE 26b Area Under the Curve Efficacy and Synergy Analysis (Days 0Through 21) for first study. 95% Synergy Confidence P Combination ScoreInterval Value Assessment Compound III-1 (3 mg/kg 16.9 (−10.8, 44.6)0.22 Additive QD) + Rituximab Compound III-1 (10 mg/kg 11.3 (−12.5,35.1) 0.33 Additive QD) + Rituximab Synergistic: score < 0, Additive:score = 0, Sub-additive: score > 0. Assessment based on whether thesynergy score was significantly different from 0.

The tumor volumes were smaller in each of the treatment groups in thesecond study compared to vehicle (Table 27a). Both combinations groupswere sub-additive relative to their respective individual treatmentswhen comparing AUC values (Table 27b).

TABLE 27a Area Under the Curve Efficacy and Synergy Analysis (Days 0Through 21) for second study. Average percent change in the area underthe log₁₀ photon flux vs day curves (AUC) relative to the mean AUC ofthe vehicle group. Pct Decrease in AUC Relative to Mean TreatmentVehicle AUC Vehicle — Compound III-1 (10 mg/kg, PO, BID) 94.0 CompoundIII-1 (20 mg/kg, PO, BID) 96.6 Rituximab (10 mg/kg, IV, QW) 41.3Compound III-1 (10 mg/kg) + 98.5 Rituximab (10 mg/kg) Compound III-1 (20mg/kg) + 100.2 Rituximab (10 mg/kg)

TABLE 27b Area Under the Curve Efficacy and Synergy Analysis (Days 0Through 21) for second study. 95% Synergy Confidence P Combination ScoreInterval Value Assessment Compound III-1 (10 mg/kg 36.8 (12.4, 61.2)0.005 Sub-Additive QD) + Rituximab Compound III-1 (20 mg/kg 37.7 (15.5,59.9) 0.003 Sub-Additive QD) + Rituximab Synergistic: score < 0,Additive: score = 0, Sub-additive: score > 0. Assessment based onwhether the synergy score was significantly different from 0.

At the end of dosing on Day 21 of the 1st study, body weight loss wasless than 5% for all groups (Table 25). In the second study, however,treatment with Compound III-1 at 20 mg/kg on a BID schedule and thecombination treatment of Compound III-1 at 20 mg/kg BID with rituximabat 10 mg/kg QW resulted in mean maximum body weight losses of 8.9% (Day9) and 12.2% (Day 9) respectively. This effect was managed by giving allanimals in these groups a 5 day dose holiday (Day 9 through Day 13);animals then regained body weight. No other treatment group exhibited amaximum body weight loss greater than 3.9% (Table 25).

While the foregoing invention has been described in some detail forpurposes of clarity and understanding, these particular embodiments areto be considered as illustrative and not restrictive. It will beappreciated by one skilled in the art from a reading of this disclosurethat various changes in form and detail can be made without departingfrom the true scope of the invention, which is to be defined by theappended claims rather than by the specific embodiments.

The patent and scientific literature referred to herein establishesknowledge that is available to those with skill in the art. Unlessotherwise defined, all technical and scientific terms used herein havethe same meaning as commonly understood by one of ordinary skill in theart to which this invention belongs. The issued patents, applications,and references that are cited herein are hereby incorporated byreference to the same extent as if each was specifically andindividually indicated to be incorporated by reference. In the case ofinconsistencies, the present disclosure, including definitions, willcontrol.

1. A method of treating a patient suffering from a hematologicalmalignancy, comprising administering to the subject a therapeuticallyeffective amount of an Aurora kinase inhibitor simultaneously with orconsecutively with an anti-CD20 antibody.
 2. The method of claim 1,wherein the hematological malignancy is selected from the groupconsisting of lymphoma, leukemia and multiple myeloma.
 3. The method ofclaim 2, wherein the lymphoma is selected from the group consisting ofB-cell lymphoma, Non-Hodgkin's lymphoma and mantle cell lymphoma.
 4. Themethod of claim 1, wherein the anti-CD20 antibody is rituximab.
 5. Themethod of claim 4, wherein the patient was treated previously with ananti-CD20 antibody.
 6. The method of claim 1, wherein the Aurora kinaseinhibitor is an Aurora A kinase specific inhibitor.
 7. The method ofclaim 6, wherein the Aurora A kinase specific inhibitor is characterizedby formula (I):

or a pharmaceutically acceptable salt thereof; wherein: Ring A is asubstituted or unsubstituted 5- or 6-membered aryl, heteroaryl,cycloaliphatic, or heterocyclyl ring; Ring B is a substituted orunsubstituted aryl, heteroaryl, cycloaliphatic, or heterocyclyl ring;Ring C is a substituted or unsubstituted aryl, heteroaryl, heterocyclyl,or cycloaliphatic ring; R^(e) is hydrogen, —OR⁵, —N(R⁴)₂, —SR⁵, or aC₁₋₃ aliphatic optionally substituted with R³ or R⁷; each of R^(x) andR^(y) independently is hydrogen, fluoro, or an optionally substitutedC₁₋₆ aliphatic; or R^(x) and R^(y), taken together with the carbon atomto which they are attached, form an optionally substituted 3- to6-membered cycloaliphatic ring; each R³ independently is selected fromthe group consisting of -halo, —OH, —O(C₁₋₃ alkyl), —CN, —N(R⁴)₂,—C(O)(C₁₋₃ alkyl), —CO₂H, —CO₂(C₁₋₃ alkyl), —C(O)NH₂, and —C(O)NH(C₁₋₃alkyl); each R⁴ independently is hydrogen or an optionally substitutedaliphatic, aryl, heteroaryl, or heterocyclyl group; or two R⁴ on thesame nitrogen atom, taken together with the nitrogen atom, form anoptionally substituted 5- to 6-membered heteroaryl or 4- to 8-memberedheterocyclyl ring having, in addition to the nitrogen atom, 0-2 ringheteroatoms selected from N, O, and S; each R⁵ independently is hydrogenor an optionally substituted aliphatic, aryl, heteroaryl, orheterocyclyl group; and each R⁷ independently is an optionallysubstituted aryl, heterocyclyl, or heteroaryl group.
 8. The method ofclaim 6, wherein the Aurora A kinase specific inhibitor is characterizedby formula (III):

or a pharmaceutically acceptable salt thereof; wherein: R^(a) isselected from the group consisting of C₁₋₃ aliphatic, C₁₋₃fluoroaliphatic, —R², and -T-R²; T is a C₁₋₃ alkylene chain optionallysubstituted with fluoro; R¹ is an optionally substituted aryl,heteroaryl, or heterocyclyl group; R² is selected from the groupconsisting of halo, —C═C—R³, —CH═CH—R³, —N(R⁴)₂, and —OR⁵; R³ ishydrogen or an optionally substituted aliphatic, aryl, heteroaryl, orheterocyclyl group; each R⁴ independently is hydrogen or an optionallysubstituted aliphatic, aryl, heteroaryl, or heterocyclyl group; or twoR⁴ on the same nitrogen atom, taken together with the nitrogen atom forman optionally substituted 5- to 6-membered heteroaryl or 4- to8-membered heterocyclyl ring having, in addition to the nitrogen atom,0-2 ring heteroatoms selected from N, O, and S; R⁵ is hydrogen or anoptionally substituted aliphatic, aryl, heteroaryl, or heterocyclylgroup; and R^(b) is selected from the group consisting of fluoro,chloro, —CH_(S), —CF₃, —OH, —OCH₃, —OCF₃, —OCH₂CH₃, and —OCH₂CF₃.
 9. Themethod of claim 6, wherein the Aurora A kinase specific inhibitor is4-{[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino}-2-methoxybenzoicacid.